Login | Register

Effects of β₂-Adrenergic Receptor Signaling Pathways on Adaptive T Cell Responses, Implications for Inflammation and Cancer Immunity

Title:

Effects of β₂-Adrenergic Receptor Signaling Pathways on Adaptive T Cell Responses, Implications for Inflammation and Cancer Immunity

Hajiaghayi, Mehri ORCID: https://orcid.org/0000-0001-6607-7009 (2025) Effects of β₂-Adrenergic Receptor Signaling Pathways on Adaptive T Cell Responses, Implications for Inflammation and Cancer Immunity. PhD thesis, Concordia University.

[thumbnail of Hajiaghayi_PhD_F2025.pdf]
Preview
Text (application/pdf)
Hajiaghayi_PhD_F2025.pdf - Accepted Version
Available under License Spectrum Terms of Access.
3MB

Abstract

Background: Stress is a powerful regulator of physiology with broad effects on immune function. Adaptive immunity detects and responds to new pathogens and cancerous cells. T cells are key regulators of this system, coordinating immune responses and maintaining long-term memory. They express β₂-adrenergic receptors (β₂-AR), which respond to stress hormones like adrenaline and noradrenaline, as well as various pharmacological agents. Activation of β₂-AR on T cells influences cytokine production, differentiation, and effector functions.
To model how stress impacts adaptive T cell immunity, I investigated how β₂-AR signaling modulates T cell responses using primary human samples stimulated with different β₂-adrenergic ligands. β₂-AR signals through two main intracellular pathways: the canonical Gs–cAMP–PKA route and the alternative β–arrestin–mediated biased pathway. This project asked how selective activation of these distinct pathways, from the same receptor, differently regulates T cell behavior. I approached the question from a basic signaling perspective and extended it to an applied context in cancer immunotherapy.
Results: In brief, engaging the canonical β₂-AR pathway augmented pro-inflammatory cytokine production in T cells. In contrast, biased β₂-AR signaling suppressed these inflammatory responses. Furthermore, the biased β₂-AR signaling restored cytotoxic function in dysfunctional T cells, which prolonged their anti-cancer potential.

Relevance: These findings highlight β₂-AR as a modifiable target that enhances or suppresses T cell behavior depending on the signaling route engaged. This work offers insight into how stress-responsive pathways shape immunity and provides a conceptual foundation for developing next-generation immunomodulatory strategies in cancer therapy.

Divisions:Concordia University > Faculty of Arts and Science > Biology
Item Type:Thesis (PhD)
Authors:Hajiaghayi, Mehri
Institution:Concordia University
Degree Name:Ph. D.
Program:Biology
Date:29 May 2025
Thesis Supervisor(s):Darlington, Peter John
Keywords:β₂-Adrenergic Receptor, T Cell, Inflammation, Cancer Immunity, Memory T helper cells, Nebivolol, Terbutaline, Exhaustion
ID Code:995825
Deposited By: Mehri Hajiaghayi
Deposited On:04 Nov 2025 15:15
Last Modified:04 Nov 2025 15:15

References:

1. McNeela EA, Mills KH. Manipulating the immune system: humoral versus cell-mediated immunity. Advanced drug delivery reviews. 2001;51(1-3):43-54.
2. Bonilla FA, Oettgen HC. Adaptive immunity. Journal of Allergy and Clinical Immunology. 2010;125(2):S33-S40.
3. Grossman Z, Paul WE. Dynamic tuning of lymphocytes: physiological basis, mechanisms, and function. Annual Review of Immunology. 2015;33(1):677-713.
4. Sanders VM. The beta2-adrenergic receptor on T and B lymphocytes: do we understand it yet? Brain, behavior, and immunity. 2012;26(2):195-200.
5. Guereschi MG, Araujo LP, Maricato JT, Takenaka MC, Nascimento VM, Vivanco BC, et al. Beta2‐adrenergic receptor signaling in CD 4+ F oxp3+ regulatory T cells enhances their suppressive function in a PKA‐dependent manner. European journal of immunology. 2013;43(4):1001-12.
6. Sanders VM, Baker RA, Ramer-Quinn DS, Kasprowicz DJ, Fuchs BA, Street NE. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. The Journal of Immunology. 1997;158(9):4200-10.
7. Ramer-Quinn DS, Baker RA, Sanders VM. Activated T helper 1 and T helper 2 cells differentially express the beta-2-adrenergic receptor: a mechanism for selective modulation of T helper 1 cell cytokine production. The Journal of Immunology. 1997;159(10):4857-67.
8. Ramer-Quinn DS, Swanson MA, Lee WT, Sanders VM. Cytokine production by naive and primary effector CD4+ T cells exposed to norepinephrine. Brain, behavior, and immunity. 2000;14(4):239-55.
9. Riether C, Kavelaars A, Wirth T, Pacheco-López G, Doenlen R, Willemen H, et al. Stimulation of β2-adrenergic receptors inhibits calcineurin activity in CD4+ T cells via PKA–AKAP interaction. Brain, behavior, and immunity. 2011;25(1):59-66.
10. Pierce KL, Lefkowitz RJ. Classical and new roles of β-arrestins in the regulation of G-protein-coupled receptors. Nature reviews neuroscience. 2001;2(10):727-33.
11. Robert C. A decade of immune-checkpoint inhibitors in cancer therapy. Nature communications. 2020;11(1):3801.
12. Turvey SE, Broide DH. Innate immunity. Journal of Allergy and Clinical Immunology. 2010;125(2):S24-S32.
13. Chaplin DD. Overview of the immune response. Journal of allergy and clinical immunology. 2010;125(2):S3-S23.
14. Abós B, Bailey C, Tafalla C. Adaptive immunity. Principles of fish immunology: from cells and molecules to host protection: Springer; 2022. p. 105-40.
15. Roche PA, Furuta K. The ins and outs of MHC class II-mediated antigen processing and presentation. Nature Reviews Immunology. 2015;15(4):203-16.
16. Neefjes J, Jongsma ML, Paul P, Bakke O. Towards a systems understanding of MHC class I and MHC class II antigen presentation. Nature reviews immunology. 2011;11(12):823-36.
17. Jiang N, Malone M, Chizari S. Antigen‐specific and cross‐reactive T cells in protection and disease. Immunological reviews. 2023;316(1):120-35.
18. Samelson LE. Signal transduction mediated by the T cell antigen receptor: the role of adapter proteins. Annual review of immunology. 2002;20(1):371-94.
19. Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW. The organizing principle in the formation of the T cell receptor-CD3 complex. Cell. 2002;111(7):967-79.
20. Wange RL, Samelson LE. Complex complexes: signaling at the TCR. Immunity. 1996;5(3):197-205.
21. Ellmeier W, Haust L, Tschismarov R. Transcriptional control of CD4 and CD8 coreceptor expression during T cell development. Cellular and Molecular Life Sciences. 2013;70:4537-53.
22. Acres RB, Conlon P, Mochizuki D, Gallis B. Rapid phosphorylation and modulation of the T4 antigen on cloned helper T cells induced by phorbol myristate acetate or antigen. Journal of Biological Chemistry. 1986;261(34):16210-4.
23. Shin J, Doyle C, Yang Z, Kappes D, Strominger J. Structural features of the cytoplasmic region of CD4 required for internalization. The EMBO Journal. 1990;9(2):425-34.
24. Isakov N, Wange RL, Burgess WH, Watts JD, Aebersold R, Samelson LE. ZAP-70 binding specificity to T cell receptor tyrosine-based activation motifs: the tandem SH2 domains of ZAP-70 bind distinct tyrosine-based activation motifs with varying affinity. Journal of experimental medicine. 1995;181(1):375-80.
25. Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE. LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation. Cell. 1998;92(1):83-92.
26. Wardenburg JB, Fu C, Jackman JK, Flotow H, Wilkinson SE, Williams DH, et al. Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function. Journal of Biological Chemistry. 1996;271(33):19641-4.
27. Binder C, Cvetkovski F, Sellberg F, Berg S, Paternina Visbal H, Sachs DH, et al. CD2 immunobiology. Frontiers in immunology. 2020;11:1090.
28. Siokis A, Robert PA, Demetriou P, Dustin ML, Meyer-Hermann M. F-actin-driven CD28-CD80 localization in the immune synapse. Cell reports. 2018;24(5):1151-62.
29. Acuto O, Michel F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nature Reviews Immunology. 2003;3(12):939-51.
30. Xia F, Qian C-R, Xun Z, Hamon Y, Sartre A-M, Formisano A, et al. TCR and CD28 concomitant stimulation elicits a distinctive calcium response in naive T cells. Frontiers in immunology. 2018;9:2864.
31. Beach D, Gonen R, Bogin Y, Reischl IG, Yablonski D. Dual role of SLP-76 in mediating T cell receptor-induced activation of phospholipase C-γ1. Journal of Biological Chemistry. 2007;282(5):2937-46.
32. Berridge MJ. Inositol trisphosphate and calcium signalling mechanisms. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research. 2009;1793(6):933-40.
33. Macian F. NFAT proteins: key regulators of T-cell development and function. Nature Reviews Immunology. 2005;5(6):472-84.
34. Wherry EJ, Ha S-J, Kaech SM, Haining WN, Sarkar S, Kalia V, et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity. 2007;27(4):670-84.
35. Sun L, Deng L, Ea C-K, Xia Z-P, Chen ZJ. The TRAF6 ubiquitin ligase and TAK1 kinase mediate IKK activation by BCL10 and MALT1 in T lymphocytes. Molecular cell. 2004;14(3):289-301.
36. Zhou H, Wertz I, O'Rourke K, Ultsch M, Seshagiri S, Eby M, et al. Bcl10 activates the NF-κB pathway through ubiquitination of NEMO. Nature. 2004;427(6970):167-71.
37. Blanchett S, Boal-Carvalho I, Layzell S, Seddon B. NF-κB and extrinsic cell death pathways–Entwined do-or-die decisions for T cells. Trends in immunology. 2021;42(1):76-88.
38. Ebinu JO, Bottorff DA, Chan EY, Stang SL, Dunn RJ, Stone JC. RasGRP, a Ras guanyl nucleotide-releasing protein with calcium-and diacylglycerol-binding motifs. Science. 1998;280(5366):1082-6.
39. Kolch W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nature reviews Molecular cell biology. 2005;6(11):827-37.
40. Chiang GG, Sefton BM. Specific dephosphorylation of the Lck tyrosine protein kinase at Tyr-394 by the SHP-1 protein-tyrosine phosphatase. Journal of Biological Chemistry. 2001;276(25):23173-8.
41. McNeill L, Salmond RJ, Cooper JC, Carret CK, Cassady-Cain RL, Roche-Molina M, et al. The differential regulation of Lck kinase phosphorylation sites by CD45 is critical for T cell receptor signaling responses. Immunity. 2007;27(3):425-37.
42. DeFord-Watts LM, Tassin TC, Becker AM, Medeiros JJ, Albanesi JP, Love PE, et al. The cytoplasmic tail of the T cell receptor CD3 ε subunit contains a phospholipid-binding motif that regulates T cell functions. The Journal of Immunology. 2009;183(2):1055-64.
43. Zygmunt B, Veldhoen M. T helper cell differentiation: more than just cytokines. Advances in immunology. 2011;109:159-96.
44. Pennington DJ, Vermijlen D, Wise EL, Clarke SL, Tigelaar RE, Hayday AC. The integration of conventional and unconventional T cells that characterizes cell‐mediated responses. Advances in immunology. 2005;87:27-59.
45. Kumar BV, Connors TJ, Farber DL. Human T cell development, localization, and function throughout life. Immunity. 2018;48(2):202-13.
46. Sanders ME, Makgoba MW, Shaw S. Human naive and memory T cells: reinterpretation of helper-inducer and suppressor-inducer subsets. Immunology today. 1988;9(7-8):195-9.
47. Yamane H, Paul WE. Early signaling events that underlie fate decisions of naive CD 4+ T cells toward distinct T‐helper cell subsets. Immunological reviews. 2013;252(1):12-23.
48. Burnet SFM. The clonal selection theory of acquired immunity: Vanderbilt University Press Nashville; 1959.
49. Linsley PS, Clark EA, Ledbetter JA. T-cell antigen CD28 mediates adhesion with B cells by interacting with activation antigen B7/BB-1. Proceedings of the National Academy of Sciences. 1990;87(13):5031-5.
50. Leitner J, Herndler-Brandstetter D, Zlabinger GJ, Grubeck-Loebenstein B, Steinberger P. CD58/CD2 is the primary costimulatory pathway in human CD28− CD8+ T cells. The Journal of Immunology. 2015;195(2):477-87.
51. Scott P. IL-12: initiation cytokine for cell-mediated immunity. Science. 1993;260(5107):496-7.
52. Korn T, Bettelli E, Oukka M, Kuchroo VK. IL-17 and Th17 Cells. Annual review of immunology. 2009;27:485-517.
53. Andreu-Sanz D, Kobold S. Role and potential of different T helper cell subsets in adoptive cell therapy. Cancers. 2023;15(6):1650.
54. Szabo SJ, Kim ST, Costa GL, Zhang X, Fathman CG, Glimcher LH. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell. 2000;100(6):655-69.
55. Simpson DS, Pang J, Weir A, Kong IY, Fritsch M, Rashidi M, et al. Interferon-γ primes macrophages for pathogen ligand-induced killing via a caspase-8 and mitochondrial cell death pathway. Immunity. 2022;55(3):423-41. e9.
56. Martín-Fontecha A, Thomsen LL, Brett S, Gerard C, Lipp M, Lanzavecchia A, et al. Induced recruitment of NK cells to lymph nodes provides IFN-γ for TH1 priming. Nature immunology. 2004;5(12):1260-5.
57. Pearce EJ, Caspar P, Grzych J-M, Lewis FA, Sher A. Pillars article: downregulation of Th1 cytokine production accompanies induction of Th2 responses by a parasitic helminth, Schistosoma mansoni. J. Exp. Med. 1991. 173: 159-166. Journal of Immunology (Baltimore, Md: 1950). 2012;189(3):1104-11.
58. Tokura Y, Phadungsaksawasdi P, Ito T. Atopic dermatitis as Th2 disease revisited. Journal of Cutaneous Immunology and Allergy. 2018;1(5):158-64.
59. Ouyang W, Löhning M, Gao Z, Assenmacher M, Ranganath S, Radbruch A, et al. Stat6-independent GATA-3 autoactivation directs IL-4-independent Th2 development and commitment. Immunity. 2000;12(1):27-37.
60. Vahedi G, C. Poholek A, Hand TW, Laurence A, Kanno Y, O'Shea JJ, et al. Helper T‐cell identity and evolution of differential transcriptomes and epigenomes. Immunological reviews. 2013;252(1):24-40.
61. Murphy KM, Stockinger B. Effector T cell plasticity: flexibility in the face of changing circumstances. Nature immunology. 2010;11(8):674-80.
62. Maddur MS, Miossec P, Kaveri SV, Bayry J. Th17 cells: biology, pathogenesis of autoimmune and inflammatory diseases, and therapeutic strategies. The American journal of pathology. 2012;181(1):8-18.
63. Gaffen SL. Structure and signalling in the IL-17 receptor family. Nature Reviews Immunology. 2009;9(8):556-67.
64. Hot A, Miossec P. Effects of interleukin (IL)-17A and IL-17F in human rheumatoid arthritis synoviocytes. Annals of the rheumatic diseases. 2011;70(5):727-32.
65. Bettelli E, Korn T, Oukka M, Kuchroo VK. Induction and effector functions of TH17 cells. Nature. 2008;453(7198):1051-7.
66. Singh SP, Zhang HH, Foley JF, Hedrick MN, Farber JM. Human T cells that are able to produce IL-17 express the chemokine receptor CCR6. The Journal of Immunology. 2008;180(1):214-21.
67. Bianchi E, Rogge L. The IL-23/IL-17 pathway in human chronic inflammatory diseases—new insight from genetics and targeted therapies. Genes & Immunity. 2019;20(5):415-25.
68. Hirahara K, Ghoreschi K, Laurence A, Yang X-P, Kanno Y, O'Shea JJ. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine & growth factor reviews. 2010;21(6):425-34.
69. Yang XO, Pappu BP, Nurieva R, Akimzhanov A, Kang HS, Chung Y, et al. T helper 17 lineage differentiation is programmed by orphan nuclear receptors RORα and RORγ. Immunity. 2008;28(1):29-39.
70. Wu X, Tian J, Wang S. Insight into non-pathogenic Th17 cells in autoimmune diseases. Frontiers in immunology. 2018;9:1112.
71. Kanellopoulou C, Muljo SA. Fine-tuning Th17 cells: to be or not to be pathogenic? Immunity. 2016;44(6):1241-3.
72. Raphael I, Nalawade S, Eagar TN, Forsthuber TG. T cell subsets and their signature cytokines in autoimmune and inflammatory diseases. Cytokine. 2015;74(1):5-17.
73. De Benedetti F, Prencipe G, Bracaglia C, Marasco E, Grom AA. Targeting interferon-γ in hyperinflammation: opportunities and challenges. Nature Reviews Rheumatology. 2021;17(11):678-91.
74. Bazzaz JT, Amoli MM, Taheri Z, Larijani B, Pravica V, Hutchinson IV. TNF-α and IFN-γ gene variation and genetic susceptibility to type 1 diabetes and its microangiopathic complications. Journal of Diabetes & Metabolic Disorders. 2014;13:1-7.
75. Panitch HS, Hirsch RL, Schindler J, Johnson KP. Treatment of multiple sclerosis with gamma interferon: exacerbations associated with activation of the immune system. Neurology. 1987;37(7):1097-.
76. Lee K, Min HK, Koh S-H, Lee S-H, Kim H-R, Ju JH, et al. Prognostic signature of interferon-γ and interleurkin-17A in early rheumatoid arthritis. Clin Exp Rheumatol. 2022;40(5):999-1005.
77. Paradowska-Gorycka A, Wajda A, Stypinska B, Walczuk E, Rzeszotarska E, Walczyk M, et al. Variety of endosomal TLRs and Interferons (IFN-α, IFN-β, IFN-γ) expression profiles in patients with SLE, SSc and MCTD. Clinical & Experimental Immunology. 2021;204(1):49-63.
78. Szabo SJ, Sullivan BM, Peng SL, Glimcher LH. Molecular mechanisms regulating Th1 immune responses. Annual review of immunology. 2003;21:713.
79. Flannigan KL, Ngo VL, Geem D, Harusato A, Hirota SA, Parkos CA, et al. IL-17A-mediated neutrophil recruitment limits expansion of segmented filamentous bacteria. Mucosal immunology. 2017;10(3):673-84.
80. Iwakura Y, Ishigame H, Saijo S, Nakae S. Functional specialization of interleukin-17 family members. Immunity. 2011;34(2):149-62.
81. Mazzoni A, Maggi L, Liotta F, Cosmi L, Annunziato F. Biological and clinical significance of T helper 17 cell plasticity. Immunology. 2019;158(4):287-95.
82. Annunziato F, Romagnani C, Romagnani S. The 3 major types of innate and adaptive cell-mediated effector immunity. Journal of Allergy and Clinical Immunology. 2015;135(3):626-35.
83. Schnell A, Huang L, Singer M, Singaraju A, Barilla RM, Regan BM, et al. Stem-like intestinal Th17 cells give rise to pathogenic effector T cells during autoimmunity. Cell. 2021;184(26):6281-98. e23.
84. Steel KJ, Srenathan U, Ridley M, Durham LE, Wu SY, Ryan SE, et al. Polyfunctional, proinflammatory, Tissue‐Resident memory phenotype and function of synovial Interleukin‐17A+ CD 8+ T cells in psoriatic arthritis. Arthritis & Rheumatology. 2020;72(3):435-47.
85. Roeleveld DM, Koenders MI. The role of the Th17 cytokines IL-17 and IL-22 in Rheumatoid Arthritis pathogenesis and developments in cytokine immunotherapy. Cytokine. 2015;74(1):101-7.
86. Paulissen SM, van Hamburg JP, Dankers W, Lubberts E. The role and modulation of CCR6+ Th17 cell populations in rheumatoid arthritis. Cytokine. 2015;74(1):43-53.
87. Moser T, Akgün K, Proschmann U, Sellner J, Ziemssen T. The role of TH17 cells in multiple sclerosis: Therapeutic implications. Autoimmunity reviews. 2020;19(10):102647.
88. Hwang S-H, Woo JS, Moon J, Yang S, Park J-S, Lee J, et al. IL-17 and CCR9+ α4β7–Th17 cells promote salivary gland inflammation, dysfunction, and cell death in Sjögren’s syndrome. Frontiers in Immunology. 2021;12:721453.
89. Kim SW, Kim ES, Moon CM, Park JJ, Kim TI, Kim WH, et al. Genetic polymorphisms of IL-23R and IL-17A and novel insights into their associations with inflammatory bowel disease. Gut. 2011;60(11):1527-36.
90. Huang N, Dong H, Luo Y, Shao B. Th17 cells in periodontitis and its regulation by A20. Frontiers in immunology. 2021;12:742925.
91. Zwicky P, Unger S, Becher B. Targeting interleukin-17 in chronic inflammatory disease: A clinical perspective. Journal of Experimental Medicine. 2019;217(1):e20191123.
92. Dong C. Cytokine regulation and function in T cells. Annual review of immunology. 2021;39(1):51-76.
93. Cooney LA, Fox DA. Regulation of Th17 maturation by interleukin 4. Critical Reviews™ in Immunology. 2013;33(5).
94. Saggini A, Maccauro G, Tripodi D, De Lutiis MA, Conti F, Felaco P, et al. Allergic inflammation: role of cytokines with special emphasis on IL-4. International Journal of Immunopathology and Pharmacology. 2011;24(2):305-11.
95. Malmhäll C, Bossios A, Rådinger M, Sjöstrand M, Lu Y, Lundbäck B, et al. Immunophenotyping of circulating T helper cells argues for multiple functions and plasticity of T cells in vivo in humans-possible role in asthma. PloS one. 2012;7(6):e40012.
96. Wang Y-H, Voo KS, Liu B, Chen C-Y, Uygungil B, Spoede W, et al. A novel subset of CD4+ TH2 memory/effector cells that produce inflammatory IL-17 cytokine and promote the exacerbation of chronic allergic asthma. Journal of Experimental Medicine. 2010;207(11):2479-91.
97. Meitei HT, Lal G. T cell receptor signaling in the differentiation and plasticity of CD4+ T cells. Cytokine & Growth Factor Reviews. 2023;69:14-27.
98. Lee YK, Turner H, Maynard CL, Oliver JR, Chen D, Elson CO, et al. Late developmental plasticity in the T helper 17 lineage. Immunity. 2009;30(1):92-107.
99. Bending D, De La Peña H, Veldhoen M, Phillips JM, Uyttenhove C, Stockinger B, et al. Highly purified Th17 cells from BDC2. 5NOD mice convert into Th1-like cells in NOD/SCID recipient mice. The Journal of clinical investigation. 2009;119(3):565-72.
100. Fragoulis GE, Siebert S, McInnes IB. Therapeutic targeting of IL-17 and IL-23 cytokines in immune-mediated diseases. Annual review of medicine. 2016;67(1):337-53.
101. Qian J, Galitovskiy V, Chernyavsky A, Marchenko S, Grando S. Plasticity of the murine spleen T-cell cholinergic receptors and their role in in vitro differentiation of naive CD4 T cells toward the Th1, Th2 and Th17 lineages. Genes & Immunity. 2011;12(3):222-30.
102. Leposavić G, Pilipović I, Radojević K, Pešić V, Perišić M, Kosec D. Catecholamines as immunomodulators: a role for adrenoceptor-mediated mechanisms in fine tuning of T-cell development. Autonomic Neuroscience. 2008;144(1-2):1-12.
103. Ahmed R, Bevan MJ, Reiner SL, Fearon DT. The precursors of memory: models and controversies. Nature Reviews Immunology. 2009;9(9):662-8.
104. MacLeod MK, Kappler JW, Marrack P. Memory CD4 T cells: generation, reactivation and re‐assignment. Immunology. 2010;130(1):10-5.
105. Krawczyk CM, Shen H, Pearce EJ. Functional plasticity in memory T helper cell responses. The Journal of Immunology. 2007;178(7):4080-8.
106. Raphael I, Joern RR, Forsthuber TG. Memory CD4+ T cells in immunity and autoimmune diseases. Cells. 2020;9(3):531.
107. Künzli M, Masopust D. CD4+ T cell memory. Nature immunology. 2023;24(6):903-14.
108. Sallusto F, Lenig D, Förster R, Lipp M, Lanzavecchia A. Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature. 1999;401(6754):708-12.
109. Pepper M, Pagán AJ, Igyártó BZ, Taylor JJ, Jenkins MK. Opposing signals from the Bcl6 transcription factor and the interleukin-2 receptor generate T helper 1 central and effector memory cells. Immunity. 2011;35(4):583-95.
110. Kryczek I, Zhao E, Liu Y, Wang Y, Vatan L, Szeliga W, et al. Human TH17 cells are long-lived effector memory cells. Science translational medicine. 2011;3(104):104ra0-ra0.
111. Mojtabavi N, Dekan G, Stingl G, Epstein MM. Long-lived Th2 memory in experimental allergic asthma. The Journal of Immunology. 2002;169(9):4788-96.
112. Mueller SN, Gebhardt T, Carbone FR, Heath WR. Memory T cell subsets, migration patterns, and tissue residence. Annual review of immunology. 2013;31(1):137-61.
113. Chen Y, Chauhan SK, Soo Lee H, Saban DR, Dana R. Chronic dry eye disease is principally mediated by effector memory Th17 cells. Mucosal immunology. 2014;7(1):38-45.
114. Yang J, Sundrud MS, Skepner J, Yamagata T. Targeting Th17 cells in autoimmune diseases. Trends in pharmacological sciences. 2014;35(10):493-500.
115. Vyas KJ, Shadyab AH, Lin C-D, Crum-Cianflone NF. Trends and factors associated with initial and recurrent methicillin-resistant Staphylococcus aureus (MRSA) skin and soft-tissue infections among HIV-infected persons: an 18-year study. Journal of the International Association of Providers of AIDS Care (JIAPAC). 2014;13(3):206-13.
116. Montgomerie JZ. Infections in patients with spinal cord injuries. Clinical infectious diseases. 1997;25(6):1285-90.
117. Shim R, Wen SW, Wanrooy BJ, Rank M, Thirugnanachandran T, Ho L, et al. Stroke severity, and not cerebral infarct location, increases the risk of infection. Translational stroke research. 2020;11:387-401.
118. Cerritelli F, Frasch MG, Antonelli MC, Viglione C, Vecchi S, Chiera M, et al. A review on the vagus nerve and autonomic nervous system during fetal development: searching for critical windows. Frontiers in Neuroscience. 2021;15:721605.
119. Pradhan AK, Elanchezhian M. The Biology of Neuroimmune Communication. Neuroimmune System: CRC Press; 2025. p. 1-24.
120. Weissman DG, Mendes WB. Correlation of sympathetic and parasympathetic nervous system activity during rest and acute stress tasks. International Journal of Psychophysiology. 2021;162:60-8.
121. Elenkov IJ, Wilder RL, Chrousos GP, Vizi ES. The sympathetic nerve—an integrative interface between two supersystems: the brain and the immune system. Pharmacological reviews. 2000;52(4):595-638.
122. Nance DM, Sanders VM. Autonomic innervation and regulation of the immune system (1987–2007). Brain, behavior, and immunity. 2007;21(6):736-45.
123. Bellinger DL, Lorton D, Felten SY, Felten DL. Innervation of lymphoid organs and implications in development, aging, and autoimmunity. International journal of immunopharmacology. 1992;14(3):329-44.
124. Yanagawa Y, Matsumoto M, Togashi H. Enhanced dendritic cell antigen uptake via α2 adrenoceptor-mediated PI3K activation following brief exposure to noradrenaline. The Journal of Immunology. 2010;185(10):5762-8.
125. Hervé J, Dubreil L, Tardif V, Terme M, Pogu S, Anegon I, et al. β2-Adrenoreceptor agonist inhibits antigen cross-presentation by dendritic cells. The Journal of Immunology. 2013;190(7):3163-71.
126. Strosberg A. Structure, function, and regulation of adrenergic receptors. Protein Science. 1993;2(8):1198-209.
127. Chhatar S, Lal G. Role of adrenergic receptor signalling in neuroimmune communication. Current Research in Immunology. 2021;2:202-17.
128. Fan N-W, Yu M, Wang S, Blanco T, Luznik Z, Chauhan SK, et al. Activation of α2B/2C adrenergic receptor ameliorates ocular surface inflammation through enhancing regulatory T cell function. Mucosal immunology. 2025;18(1):176-87.
129. Casale TB, Kaliner M. Demonstration that circulating human blood cells have no detectable alpha1-adrenergic receptors by radioligand binding analysis. Journal of allergy and clinical immunology. 1984;74(6):812-8.
130. Ricci A, Bronzetti E, Conterno A, Greco S, Mulatero P, Schena M, et al. α1-Adrenergic receptor subtypes in human peripheral blood lymphocytes. Hypertension. 1999;33(2):708-12.
131. Kolmus K, Tavernier J, Gerlo S. β2-Adrenergic receptors in immunity and inflammation: stressing NF-κB. Brain, behavior, and immunity. 2015;45:297-310.
132. Wu L, Tai Y, Hu S, Zhang M, Wang R, Zhou W, et al. Bidirectional role of β2-adrenergic receptor in autoimmune diseases. Frontiers in pharmacology. 2018:1313.
133. Araujo LP, Maricato JT, Guereschi MG, Takenaka MC, Nascimento VM, de Melo FM, et al. The sympathetic nervous system mitigates CNS autoimmunity via β2-adrenergic receptor signaling in immune cells. Cell reports. 2019;28(12):3120-30. e5.
134. Sanders VM. Adrenergic receptors on T and B lymphocytes: Evidence, function, and clinical implications. Clinical Neuroscience Research. 2006;6(1-2):34-41.
135. Slota C, Shi A, Chen G, Bevans M, Weng N-p. Norepinephrine preferentially modulates memory CD8 T cell function inducing inflammatory cytokine production and reducing proliferation in response to activation. Brain, behavior, and immunity. 2015;46:168-79.
136. Sanders VM, Straub RH. Norepinephrine, the β-adrenergic receptor, and immunity. Brain, behavior, and immunity. 2002;16(4):290-332.
137. Heijink IH, Vellenga E, Borger P, Postma DS, Monchy JGd, Kauffman HF. Polarized Th1 and Th2 cells are less responsive to negative feedback by receptors coupled to the AC/cAMP system compared to freshly isolated T cells. British journal of pharmacology. 2003;138(8):1441-50.
138. Goleva E, Dunlap A, Leung DY. Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with β2-adrenergic agonists. Journal of allergy and clinical immunology. 2004;114(1):183-91.
139. Heijink I, Van Den Berge M, Vellenga E, De Monchy J, Postma D, Kauffman H. Altered β2‐adrenergic regulation of T cell activity after allergen challenge in asthma. Clinical & Experimental Allergy. 2004;34(9):1356-63.
140. Dhabhar FS, Viswanathan K. Short-term stress experienced at time of immunization induces a long-lasting increase in immunologic memory. American Journal of Physiology-Regulatory, Integrative and Comparative Physiology. 2005;289(3):R738-R44.
141. Kohm AP, Sanders VM. Norepinephrine and β2-adrenergic receptor stimulation regulate CD4+ T and B lymphocyte function in vitro and in vivo. Pharmacological reviews. 2001;53(4):487-525.
142. Estrada LD, Ağaç D, Farrar JD. Sympathetic neural signaling via the β2‐adrenergic receptor suppresses T‐cell receptor‐mediated human and mouse CD8+ T‐cell effector function. European journal of immunology. 2016;46(8):1948-58.
143. Zalli A, Bosch J, Goodyear O, Riddell N, McGettrick H, Moss P, et al. Targeting ß2 adrenergic receptors regulate human T cell function directly and indirectly. Brain, behavior, and immunity. 2015;45:211-8.
144. Swanson MA, Lee WT, Sanders VM. IFN-γ production by Th1 cells generated from naive CD4+ T cells exposed to norepinephrine. The Journal of Immunology. 2001;166(1):232-40.
145. Panina-Bordignon P, Mazzeo D, Lucia P, D'Ambrosio D, Lang R, Fabbri L, et al. Beta2-agonists prevent Th1 development by selective inhibition of interleukin 12. The Journal of clinical investigation. 1997;100(6):1513-9.
146. Takenaka MC, Araujo LP, Maricato JT, Nascimento VM, Guereschi MG, Rezende RM, et al. Norepinephrine Controls Effector T Cell Differentiation through β2-Adrenergic Receptor–Mediated Inhibition of NF-κB and AP-1 in Dendritic Cells. The Journal of Immunology. 2016;196(2):637-44.
147. Melnikov M, Rogovskii V, Sviridova A, Lopatina A, Pashenkov M, Boyko A. The dual role of the β2-adrenoreceptor in the modulation of IL-17 and IFN-γ production by T cells in multiple sclerosis. International Journal of Molecular Sciences. 2022;23(2):668.
148. Ritchie AI, Singanayagam A, Wiater E, Edwards MR, Montminy M, Johnston SL. β2-Agonists enhance asthma-relevant inflammatory mediators in human airway epithelial cells. American Journal of Respiratory Cell and Molecular Biology. 2018;58(1):128-32.
149. Loza MJ, Foster S, Peters SP, Penn RB. Beta-agonists modulate T-cell functions via direct actions on type 1 and type 2 cells. Blood. 2006;107(5):2052-60.
150. Manni M, Granstein RD, Maestroni G. β2-Adrenergic agonists bias TLR-2 and NOD2 activated dendritic cells towards inducing an IL-17 immune response. Cytokine. 2011;55(3):380-6.
151. Carvajal Gonczi CM, Tabatabaei Shafiei M, East A, Martire E, Maurice‐Ventouris MH, Darlington PJ. Reciprocal modulation of helper Th1 and Th17 cells by the β2‐adrenergic receptor agonist drug terbutaline. The FEBS journal. 2017;284(18):3018-28.
152. Lu J-H, Rui X-X, Wang T-T, Wang X-Q, Peng Y-P, Qiu Y-H. Activation of β2-adrenergic Receptor Alleviates Collagen-induced Arthritis by Ameliorating Th17/Treg Imbalance. Iranian Journal of Immunology. 2023;20(1):16-25.
153. Duan B, Davis R, Sadat EL, Collins J, Sternweis PC, Yuan D, et al. Distinct roles of adenylyl cyclase VII in regulating the immune responses in mice. The Journal of Immunology. 2010;185(1):335-44.
154. Barton K, Muthusamy N, Chanyangam M, Fischer C, Clendenin C, Leiden JM. Defective thymocyte proliferation and IL-2 production in transgenic mice expressing a dominant-negative form of CREB. Nature. 1996;379(6560):81-5.
155. Wang X, Ni L, Chang D, Lu H, Jiang Y, Kim B-S, et al. Cyclic AMP-responsive element-binding protein (CREB) is critical in autoimmunity by promoting Th17 but inhibiting Treg cell differentiation. EBioMedicine. 2017;25:165-74.
156. Meltzer JC, MacNeil BJ, Sanders V, Pylypas S, Jansen AH, Greenberg AH, et al. Contribution of the adrenal glands and splenic nerve to LPS-induced splenic cytokine production in the rat. Brain, Behavior, and Immunity. 2003;17(6):482-97.
157. Page C, Spina D. Phosphodiesterase inhibitors in the treatment of inflammatory diseases. Phosphodiesterases as Drug Targets. 2011:391-414.
158. Luttrell LM, Gesty-Palmer D. Beyond desensitization: physiological relevance of arrestin-dependent signaling. Pharmacological reviews. 2010;62(2):305-30.
159. Watari K, Nakaya M, Kurose H. Multiple functions of G protein-coupled receptor kinases. Journal of molecular signaling. 2014;9(1):1-9.
160. Tran TM, Friedman J, Qunaibi E, Baameur F, Moore RH, Clark RB. Characterization of agonist stimulation of cAMP-dependent protein kinase and G protein-coupled receptor kinase phosphorylation of the β2-adrenergic receptor using phosphoserine-specific antibodies. Molecular pharmacology. 2004;65(1):196-206.
161. Lorton D, Bellinger DL. Molecular mechanisms underlying β-adrenergic receptor-mediated cross-talk between sympathetic neurons and immune cells. International journal of molecular sciences. 2015;16(3):5635-65.
162. Glaser KM, Tarrant TK, Lämmermann T. Combinatorial depletions of G-protein coupled receptor kinases in immune cells identify pleiotropic and cell type-specific functions. Frontiers in immunology. 2022;13:1039803.
163. Kenakin T. Principles: receptor theory in pharmacology. Trends in pharmacological sciences. 2004;25(4):186-92.
164. Jordan VC, Phelps E, Lindgren JU. Effects of anti-estrogens on bone in castrated and intact female rats. Breast cancer research and treatment. 1987;10:31-5.
165. Erickson CE, Gul R, Blessing CP, Nguyen J, Liu T, Pulakat L, et al. The β-blocker nebivolol is a GRK/β-arrestin biased agonist. PloS one. 2013;8(8):e71980.
166. Wisler JW, DeWire SM, Whalen EJ, Violin JD, Drake MT, Ahn S, et al. A unique mechanism of β-blocker action: carvedilol stimulates β-arrestin signaling. Proceedings of the National Academy of Sciences. 2007;104(42):16657-62.
167. Kenakin T, Christopoulos A. Signalling bias in new drug discovery: detection, quantification and therapeutic impact. Nature reviews Drug discovery. 2013;12(3):205-16.
168. Beng H, Zhang H, Jayachandra R, Li J, Wu J, Tan W. Enantioselective resolution of Rac‐terbutaline and evaluation of optically pure R‐terbutaline hydrochloride as an efficient anti‐asthmatic drug. Chirality. 2018;30(6):759-68.
169. Lu K, Chen X, Zhu W, Mao X, Yang Y, Qiu J, et al. Terbutaline alleviates the lung injury in the neonatal rats exposed to endotoxin: Potential roles of epithelial sodium channels. Pediatric Pulmonology. 2019;54(3):280-8.
170. Keränen T, Hömmö T, Moilanen E, Korhonen R. β2-receptor agonists salbutamol and terbutaline attenuated cytokine production by suppressing ERK pathway through cAMP in macrophages. Cytokine. 2017;94:1-7.
171. Van de Water A, Janssens W, Van Neuten J, Xhonneux R, De Cree J, Verhaegen H, et al. Pharmacological and Hemodynamic Profile of Nebivolol,* a Chemically Novel, Potent, and Selective β1-Adrenergic Antagonist. Journal of cardiovascular pharmacology. 1988;11(5):552-63.
172. Chen L, Flies DB. Molecular mechanisms of T cell co-stimulation and co-inhibition. Nature reviews immunology. 2013;13(4):227-42.
173. Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, et al. Inflammation directs memory precursor and short-lived effector CD8+ T cell fates via the graded expression of T-bet transcription factor. Immunity. 2007;27(2):281-95.
174. Mittrücker H-W, Visekruna A, Huber M. Heterogeneity in the differentiation and function of CD8+ T cells. Archivum immunologiae et therapiae experimentalis. 2014;62:449-58.
175. Kalinichenko VV, Mokyr MB, Graf LH, Cohen RL, Chambers DA. Norepinephrine-mediated inhibition of antitumor cytotoxic T lymphocyte generation involves a β-adrenergic receptor mechanism and decreased TNF-α gene expression. The Journal of Immunology. 1999;163(5):2492-9.
176. Huang W, Wang J, Liu C, Yang C, Chen Z, Ding J, et al. Norepinephrine promotes activated B cells to identify and kill effector CD8+ T cells through FasL/Fas pathway in spleen mononuclear cells isolated from experimental autoimmune encephalomyelitis. Brain, Behavior, and Immunity. 2025;125:294-307.
177. Bucsek MJ, Qiao G, MacDonald CR, Giridharan T, Evans L, Niedzwecki B, et al. β-Adrenergic signaling in mice housed at standard temperatures suppresses an effector phenotype in CD8+ T cells and undermines checkpoint inhibitor therapy. Cancer research. 2017;77(20):5639-51.
178. Hashimoto M, Kamphorst AO, Im SJ, Kissick HT, Pillai RN, Ramalingam SS, et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annual review of medicine. 2018;69(1):301-18.
179. Blank CU, Haining WN, Held W, Hogan PG, Kallies A, Lugli E, et al. Defining ‘T cell exhaustion’. Nature Reviews Immunology. 2019;19(11):665-74.
180. Sharpe AH, Pauken KE. The diverse functions of the PD1 inhibitory pathway. Nature Reviews Immunology. 2018;18(3):153-67.
181. LaFleur MW, Muroyama Y, Drake CG, Sharpe AH. Inhibitors of the PD-1 pathway in tumor therapy. The Journal of Immunology. 2018;200(2):375-83.
182. Im SJ, Hashimoto M, Gerner MY, Lee J, Kissick HT, Burger MC, et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature. 2016;537(7620):417-21.
183. Ruffo E, Wu RC, Bruno TC, Workman CJ, Vignali DA, editors. Lymphocyte-activation gene 3 (LAG3): The next immune checkpoint receptor. Seminars in immunology; 2019: Elsevier.
184. Huang C-T, Workman CJ, Flies D, Pan X, Marson AL, Zhou G, et al. Role of LAG-3 in regulatory T cells. Immunity. 2004;21(4):503-13.
185. Malavasi F, Deaglio S, Funaro A, Ferrero E, Horenstein AL, Ortolan E, et al. Evolution and function of the ADP ribosyl cyclase/CD38 gene family in physiology and pathology. Physiological reviews. 2008;88(3):841-86.
186. DeRogatis JM, Neubert EN, Viramontes KM, Henriquez ML, Nicholas DA, Tinoco R. Cell-intrinsic CD38 expression sustains exhausted CD8+ T cells by regulating their survival and metabolism during chronic viral infection. Journal of Virology. 2023;97(4):e00225-23.
187. Zajac AJ, Blattman JN, Murali-Krishna K, Sourdive DJ, Suresh M, Altman JD, et al. Viral immune evasion due to persistence of activated T cells without effector function. The Journal of experimental medicine. 1998;188(12):2205-13.
188. Wherry EJ, Blattman JN, Murali-Krishna K, Van Der Most R, Ahmed R. Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. Journal of virology. 2003;77(8):4911-27.
189. Khan O, Giles JR, McDonald S, Manne S, Ngiow SF, Patel KP, et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature. 2019;571(7764):211-8.
190. Seo H, Chen J, González-Avalos E, Samaniego-Castruita D, Das A, Wang YH, et al. TOX and TOX2 transcription factors cooperate with NR4A transcription factors to impose CD8+ T cell exhaustion. Proceedings of the National Academy of Sciences. 2019;116(25):12410-5.
191. Seo W, Jerin C, Nishikawa H. Transcriptional regulatory network for the establishment of CD8+ T cell exhaustion. Experimental & molecular medicine. 2021;53(2):202-9.
192. Martinez GJ, Pereira RM, Äijö T, Kim EY, Marangoni F, Pipkin ME, et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity. 2015;42(2):265-78.
193. Man K, Gabriel SS, Liao Y, Gloury R, Preston S, Henstridge DC, et al. Transcription factor IRF4 promotes CD8+ T cell exhaustion and limits the development of memory-like T cells during chronic infection. Immunity. 2017;47(6):1129-41. e5.
194. Scharping NE, Menk AV, Moreci RS, Whetstone RD, Dadey RE, Watkins SC, et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity. 2016;45(2):374-88.
195. Bengsch B, Johnson AL, Kurachi M, Odorizzi PM, Pauken KE, Attanasio J, et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8+ T cell exhaustion. immunity. 2016;45(2):358-73.
196. Scharping NE, Rivadeneira DB, Menk AV, Vignali PD, Ford BR, Rittenhouse NL, et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nature immunology. 2021;22(2):205-15.
197. Quezada SA, Simpson TR, Peggs KS, Merghoub T, Vider J, Fan X, et al. Tumor-reactive CD4+ T cells develop cytotoxic activity and eradicate large established melanoma after transfer into lymphopenic hosts. Journal of Experimental Medicine. 2010;207(3):637-50.
198. Oh DY, Kwek SS, Raju SS, Li T, McCarthy E, Chow E, et al. Intratumoral CD4+ T cells mediate anti-tumor cytotoxicity in human bladder cancer. Cell. 2020;181(7):1612-25. e13.
199. Wei SC, Duffy CR, Allison JP. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer discovery. 2018;8(9):1069-86.
200. Sakuishi K, Apetoh L, Sullivan JM, Blazar BR, Kuchroo VK, Anderson AC. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. Journal of Experimental Medicine. 2010;207(10):2187-94.
201. Baghban R, Roshangar L, Jahanban-Esfahlan R, Seidi K, Ebrahimi-Kalan A, Jaymand M, et al. Tumor microenvironment complexity and therapeutic implications at a glance. Cell Communication and Signaling. 2020;18:1-19.
202. Baitsch L, Fuertes-Marraco SA, Legat A, Meyer C, Speiser DE. The three main stumbling blocks for anticancer T cells. Trends in immunology. 2012;33(7):364-72.
203. Martinez M, Moon EK. CAR T cells for solid tumors: new strategies for finding, infiltrating, and surviving in the tumor microenvironment. Frontiers in immunology. 2019;10:128.
204. Sun Y-P, Ke Y-L, Li X. Prognostic value of CD8+ tumor-infiltrating T cells in patients with breast cancer: a systematic review and meta-analysis. Oncology letters. 2022;25(1):39.
205. Jiang Y, Li Y, Zhu B. T-cell exhaustion in the tumor microenvironment. Cell death & disease. 2015;6(6):e1792-e.
206. Seliger B, Maeurer MJ, Ferrone S. Antigen-processing machinery breakdown and tumor growth. Immunology today. 2000;21(9):455-64.
207. Li W, Amei A, Bui F, Norouzifar S, Lu L, Wang Z. Impact of neoantigen expression and T-cell activation on breast cancer survival. Cancers. 2021;13(12):2879.
208. Hurwitz AA, Watkins SK. Immune suppression in the tumor microenvironment: a role for dendritic cell-mediated tolerization of T cells. Cancer Immunology, Immunotherapy. 2012;61:289-93.
209. Strauss L, Bergmann C, Szczepanski M, Gooding W, Johnson JT, Whiteside TL. A unique subset of CD4+ CD25highFoxp3+ T cells secreting interleukin-10 and transforming growth factor-β1 mediates suppression in the tumor microenvironment. Clinical Cancer Research. 2007;13(15):4345-54.
210. Han D, Tao J, Fu R, Shao Z. Myeloid-derived suppressor cell cytokine secretion as prognostic factor in myelodysplastic syndromes. Innate Immunity. 2020;26(8):703-15.
211. Ruffell B, Chang-Strachan D, Chan V, Rosenbusch A, Ho CM, Pryer N, et al. Macrophage IL-10 blocks CD8+ T cell-dependent responses to chemotherapy by suppressing IL-12 expression in intratumoral dendritic cells. Cancer cell. 2014;26(5):623-37.
212. Noman MZ, Janji B, Abdou A, Hasmim M, Terry S, Tan TZ, et al. The immune checkpoint ligand PD-L1 is upregulated in EMT-activated human breast cancer cells by a mechanism involving ZEB-1 and miR-200. Oncoimmunology. 2017;6(1):e1263412.
213. Kim SK, Cho SW. The evasion mechanisms of cancer immunity and drug intervention in the tumor microenvironment. Frontiers in pharmacology. 2022;13:868695.
214. Fukumura D, Xu L, Chen Y, Gohongi T, Seed B, Jain RK. Hypoxia and acidosis independently up-regulate vascular endothelial growth factor transcription in brain tumors in vivo. Cancer research. 2001;61(16):6020-4.
215. Crawford A, Angelosanto JM, Kao C, Doering TA, Odorizzi PM, Barnett BE, et al. Molecular and transcriptional basis of CD4+ T cell dysfunction during chronic infection. Immunity. 2014;40(2):289-302.
216. Budimir N, Thomas GD, Dolina JS, Salek-Ardakani S. Reversing T-cell exhaustion in cancer: lessons learned from PD-1/PD-L1 immune checkpoint blockade. Cancer immunology research. 2022;10(2):146-53.
217. Seidel JA, Otsuka A, Kabashima K. Anti-PD-1 and anti-CTLA-4 therapies in cancer: mechanisms of action, efficacy, and limitations. Frontiers in oncology. 2018;8:86.
218. Lipson EJ, Drake CG. Ipilimumab: an anti-CTLA-4 antibody for metastatic melanoma. Clinical cancer research. 2011;17(22):6958-62.
219. Cao J, Ding X, Ji J, Zhang L, Luo C. Efficacy and safety of immune checkpoint inhibitors rechallenge in advanced solid tumors: a systematic review and meta-analysis. Frontiers in Oncology. 2024;14:1475502.
220. Kwa MJ, Adams S. Checkpoint inhibitors in triple‐negative breast cancer (TNBC): Where to go from here. Cancer. 2018;124(10):2086-103.
221. Pitt JM, Vétizou M, Daillère R, Roberti MP, Yamazaki T, Routy B, et al. Resistance mechanisms to immune-checkpoint blockade in cancer: tumor-intrinsic and-extrinsic factors. Immunity. 2016;44(6):1255-69.
222. Ramos-Casals M, Brahmer JR, Callahan MK, Flores-Chávez A, Keegan N, Khamashta MA, et al. Immune-related adverse events of checkpoint inhibitors. Nature reviews Disease primers. 2020;6(1):38.
223. Birnboim-Perach R, Benhar I. Using Combination therapy to overcome diverse challenges of Immune Checkpoint Inhibitors treatment. International Journal of Biological Sciences. 2024;20(10):3911.
224. Farooq MA, Ajmal I, Hui X, Chen Y, Ren Y, Jiang W. β2-adrenergic receptor mediated inhibition of T cell function and its implications for CAR-T cell therapy. International journal of molecular sciences. 2023;24(16):12837.
225. Xiao L, Li X, Fang C, Yu J, Chen T. Neurotransmitters: promising immune modulators in the tumor microenvironment. Frontiers in Immunology. 2023;14:1118637.
226. Ouyang X, Zhu Z, Yang C, Wang L, Ding G, Jiang F. Epinephrine increases malignancy of breast cancer through p38 MAPK signaling pathway in depressive disorders. International journal of clinical and experimental pathology. 2019;12(6):1932.
227. Schuller HM, Al-Wadei HA. Neurotransmitter receptors as central regulators of pancreatic cancer. Future oncology. 2010;6(2):221-8.
228. Lee J-W, Shahzad MM, Lin YG, Armaiz-Pena G, Mangala LS, Han H-D, et al. Surgical stress promotes tumor growth in ovarian carcinoma. Clinical Cancer Research. 2009;15(8):2695-702.
229. Wrobel LJ, Gayet-Ageron A, Le Gal F-A. Effects of beta-blockers on melanoma microenvironment and disease survival in human. Cancers. 2020;12(5):1094.
230. Cohen S, Levi-Montalcini R, Hamburger V. A nerve growth-stimulating factor isolated from sarcom as 37 and 180. Proceedings of the National Academy of Sciences. 1954;40(10):1014-8.
231. Amaro F, Silva D, Reguengo H, Oliveira JC, Quintas C, Vale N, et al. β-adrenoceptor activation in breast mcf-10a cells induces a pattern of catecholamine production similar to that of tumorigenic mcf-7 cells. International Journal of Molecular Sciences. 2020;21(21):7968.
232. Qiao G, Bucsek MJ, Winder NM, Chen M, Giridharan T, Olejniczak SH, et al. β-Adrenergic signaling blocks murine CD8+ T-cell metabolic reprogramming during activation: a mechanism for immunosuppression by adrenergic stress. Cancer Immunology, Immunotherapy. 2019;68(1):11-22.
233. Qiao G, Chen M, Mohammadpour H, MacDonald CR, Bucsek MJ, Hylander BL, et al. Chronic adrenergic stress contributes to metabolic dysfunction and an exhausted phenotype in T cells in the tumor microenvironment. Cancer immunology research. 2021;9(6):651-64.
234. Gonczi CMC, Touma F, Daigneault T, Pozzebon C, Burchell-Reyes K, Darlington PJ. Modulation of IL-17A and IFNγ by β2-adrenergic agonist terbutaline and inverse-agonist nebivolol, influence of ADRB2 polymorphisms. AIMS Allergy and Immunology. 2021;5(4):222-39.
235. Maglione A, Zuccalà M, Tosi M, Clerico M, Rolla S. Host genetics and gut microbiome: perspectives for multiple sclerosis. Genes. 2021;12(8):1181.
236. Revu S, Wu J, Henkel M, Rittenhouse N, Menk A, Delgoffe GM, et al. IL-23 and IL-1β drive human Th17 cell differentiation and metabolic reprogramming in absence of CD28 costimulation. Cell reports. 2018;22(10):2642-53.
237. Borbón TY, Scorza BM, Clay GM, Lima Nobre de Queiroz F, Sariol AJ, Bowen JL, et al. Coinfection with Leishmania major and Staphylococcus aureus enhances the pathologic responses to both microbes through a pathway involving IL-17A. PLoS neglected tropical diseases. 2019;13(5):e0007247.
238. Shao T-Y, Ang WG, Jiang TT, Huang FS, Andersen H, Kinder JM, et al. Commensal Candida albicans positively calibrates systemic Th17 immunological responses. Cell host & microbe. 2019;25(3):404-17. e6.
239. Ouyang W, Kolls JK, Zheng Y. The biological functions of T helper 17 cell effector cytokines in inflammation. Immunity. 2008;28(4):454-67.
240. Zimmermann J, Nitsch L, Krauthausen M, Müller M. IL-17A facilitates entry of autoreactive T-cells and granulocytes into the CNS during EAE. NeuroMolecular Medicine. 2023;25(3):350-9.
241. Cole S, Manghera A, Burns L, Barrett J, Yager N, Rhys H, et al. Differential regulation of IL-17A and IL-17F via STAT5 contributes to psoriatic disease. Journal of Allergy and Clinical Immunology. 2023;152(3):783-98.
242. Newcomb DC, Peebles Jr RS. Th17-mediated inflammation in asthma. Current opinion in immunology. 2013;25(6):755-60.
243. Kebir H, Ifergan I, Alvarez JI, Bernard M, Poirier J, Arbour N, et al. Preferential recruitment of interferon‐γ–expressing TH17 cells in multiple sclerosis. Annals of Neurology: Official Journal of the American Neurological Association and the Child Neurology Society. 2009;66(3):390-402.
244. Noack M, Miossec P. Th17 and regulatory T cell balance in autoimmune and inflammatory diseases. Autoimmunity reviews. 2014;13(6):668-77.
245. Prajeeth CK, Kronisch J, Khorooshi R, Knier B, Toft-Hansen H, Gudi V, et al. Effectors of Th1 and Th17 cells act on astrocytes and augment their neuroinflammatory properties. Journal of Neuroinflammation. 2017;14:1-14.
246. Yasuda K, Takeuchi Y, Hirota K, editors. The pathogenicity of Th17 cells in autoimmune diseases. Seminars in immunopathology; 2019: Springer.
247. Darlington PJ, Touil T, Doucet JS, Gaucher D, Zeidan J, Gauchat D, et al. Diminished Th17 (not Th1) responses underlie multiple sclerosis disease abrogation after hematopoietic stem cell transplantation. Annals of neurology. 2013;73(3):341-54.
248. Karimi L, Eskandari N, Shaygannejad V. The effect of interferon-beta therapy on T-helper 17/miR-326 and T-helper 1/miR-29b-3p axis in relapsing-remitting multiple sclerosis patients. Neuroimmunomodulation. 2022;29(3):177-85.
249. Wu Q, Wang Q, Mao G, Dowling CA, Lundy SK, Mao-Draayer Y. Dimethyl fumarate selectively reduces memory T cells and shifts the balance between Th1/Th17 and Th2 in multiple sclerosis patients. The Journal of Immunology. 2017;198(8):3069-80.
250. Lewis BW, Amici SA, Kim H-Y, Shalosky EM, Khan AQ, Walum J, et al. Prmt5 in T cells drives Th17 responses, mixed granulocytic inflammation, and severe allergic airway inflammation. The Journal of Immunology. 2022;208(7):1525-33.
251. Wei Q, Liao J, Jiang M, Liu J, Liang X, Nong G. Relationship between Th17-mediated immunity and airway inflammation in childhood neutrophilic asthma. Allergy, Asthma & Clinical Immunology. 2021;17:1-12.
252. Peaston RT, Weinkove C. Measurement of catecholamines and their metabolites. Annals of clinical biochemistry. 2004;41(1):17-38.
253. Weis WI, Kobilka BK. The molecular basis of G protein–coupled receptor activation. Annual review of biochemistry. 2018;87(1):897-919.
254. McAlees JW, Smith LT, Erbe RS, Jarjoura D, Ponzio NM, Sanders VM. Epigenetic regulation of beta2-adrenergic receptor expression in TH1 and TH2 cells. Brain, behavior, and immunity. 2011;25(3):408-15.
255. Sanders VM, Baker RA, Ramer-Quinn DS, Kasprowicz DJ, Fuchs BA, Street NE. Differential expression of the beta2-adrenergic receptor by Th1 and Th2 clones: implications for cytokine production and B cell help. Journal of immunology (Baltimore, Md: 1950). 1997;158(9):4200-10.
256. Agarwal SK, Marshall Jr GD. β-Adrenergic modulation of human type-1/type-2 cytokine balance. Journal of allergy and clinical immunology. 2000;105(1):91-8.
257. Wahle M, Neumann R, Moritz F, Krause A, Buttgereit F, Baerwald C. Beta2-adrenergic receptors mediate the differential effects of catecholamines on cytokine production of PBMC. Journal of interferon & cytokine research. 2005;25(7):384-94.
258. Case AJ, Roessner CT, Tian J, Zimmerman MC. Mitochondrial superoxide signaling contributes to norepinephrine-mediated T-lymphocyte cytokine profiles. PloS one. 2016;11(10):e0164609.
259. Wen AY, Sakamoto KM, Miller LS. The role of the transcription factor CREB in immune function. The Journal of Immunology. 2010;185(11):6413-9.
260. Hsueh Y-P, Liang H-E, Ng S-Y, Lai M-Z. CD28-costimulation activates cyclic AMP-responsive element-binding protein in T lymphocytes. Journal of immunology (Baltimore, Md: 1950). 1997;158(1):85-93.
261. Wang X, Ni L, Chang D, Lu H, Jiang Y, Kim B-S, et al. Cyclic AMP-Responsive element-binding protein (CREB) is critical in autoimmunity by promoting Th17 but inhibiting treg cell differentiation (vol 25, pg 165, 2017). EBIOMEDICINE. 2020;57.
262. Tsai HC, Velichko S, Lee S, Wu R. Cholera toxin enhances interleukin‐17A production in both CD4+ and CD8+ cells via a cAMP/protein kinase A‐mediated interleukin‐17A promoter activation. Immunology. 2018;154(3):500-9.
263. Gonzalez GA, Montminy MR. Cyclic AMP stimulates somatostatin gene transcription by phosphorylation of CREB at serine 133. Cell. 1989;59(4):675-80.
264. Dostmann WR. (R P)‐cAMPS inhibits the cAMP‐dependent protein kinase by blocking the cAMP‐induced conformational transition. FEBS letters. 1995;375(3):231-4.
265. Lochner A, Moolman J. The many faces of H89: a review. Cardiovascular drug reviews. 2006;24(3‐4):261-74.
266. Baillie GS, Houslay MD. Arrestin times for compartmentalised cAMP signalling and phosphodiesterase-4 enzymes. Current opinion in cell biology. 2005;17(2):129-34.
267. Perry SJ, Baillie GS, Kohout TA, McPhee I, Magiera MM, Ang KL, et al. Targeting of cyclic AMP degradation to β2-adrenergic receptors by β-arrestins. Science. 2002;298(5594):834-6.
268. Lynch MJ, Baillie GS, Mohamed A, Li X, Maisonneuve C, Klussmann E, et al. RNA silencing identifies PDE4D5 as the functionally relevant cAMP phosphodiesterase interacting with βarrestin to control the protein kinase A/AKAP79-mediated switching of the β2-adrenergic receptor to activation of ERK in HEK293B2 cells. Journal of Biological Chemistry. 2005;280(39):33178-89.
269. Beltejar M-CG, Lau H-T, Golkowski MG, Ong S-E, Beavo JA. Analyses of PDE-regulated phosphoproteomes reveal unique and specific cAMP-signaling modules in T cells. Proceedings of the National Academy of Sciences. 2017;114(30):E6240-E9.
270. González‐García C, Bravo B, Ballester A, Gómez‐Pérez R, Eguiluz C, Redondo M, et al. Comparative assessment of PDE 4 and 7 inhibitors as therapeutic agents in experimental autoimmune encephalomyelitis. British Journal of Pharmacology. 2013;170(3):602-13.
271. Jimenez JL, Punzón C, Navarro Jn, Muñoz-Fernández MA, Fresno M. Phosphodiesterase 4 inhibitors prevent cytokine secretion by T lymphocytes by inhibiting nuclear factor-κB and nuclear factor of activated T cells activation. The Journal of pharmacology and experimental therapeutics. 2001;299(2):753-9.
272. Quah BJ, Parish CR. The use of carboxyfluorescein diacetate succinimidyl ester (CFSE) to monitor lymphocyte proliferation. Journal of visualized experiments: JoVE. 2010(44):2259.
273. Zhang F, Wang DZ, Boothby M, Penix L, Flavell RA, Aune TM. Regulation of the activity of IFN-γ promoter elements during Th cell differentiation. The Journal of Immunology. 1998;161(11):6105-12.
274. Hernandez JB, Chang C, LeBlanc M, Grimm D, Le Lay J, Kaestner KH, et al. The CREB/CRTC2 pathway modulates autoimmune disease by promoting Th17 differentiation. Nature communications. 2015;6(1):7216.
275. Li X, Murray F, Koide N, Goldstone J, Dann SM, Chen J, et al. Divergent requirement for Gαs and cAMP in the differentiation and inflammatory profile of distinct mouse Th subsets. The Journal of clinical investigation. 2012;122(3):963-73.
276. Darlington PJ, Stopnicki B, Touil T, Doucet J-S, Fawaz L, Roberts ME, et al. Natural killer cells regulate Th17 cells after autologous hematopoietic stem cell transplantation for relapsing remitting multiple sclerosis. Frontiers in immunology. 2018;9:834.
277. Karaszewski JW, Reder AT, Anlar B, Arnason BG. Increased high affinity beta-adrenergic receptor densities and cyclic AMP responses of CD8 cells in multiple sclerosis. Journal of neuroimmunology. 1993;43(1-2):1-7.
278. Khoury SJ, Healy BC, Kivisäkk P, Viglietta V, Egorova S, Guttmann CR, et al. A randomized controlled double-masked trial of albuterol add-on therapy in patients with multiple sclerosis. Archives of neurology. 2010;67(9):1055-61.
279. Borchard U. The role of the sympathetic nervous system in cardiovascular disease. Journal of Clinical and Basic Cardiology. 2001;4(3):175-7.
280. Karemaker JM. An introduction into autonomic nervous function. Physiological measurement. 2017;38(5):R89.
281. Madden KS. Catecholamines, sympathetic innervation, and immunity. Brain, behavior, and immunity. 2003;17(1):5-10.
282. Del Rey A, Besedovsky H. Sympathetic-immune interactions during different types of immune challenge. Neuroimmunomodulation. 2023;31(1):1-11.
283. Naqvi S, Martin KJ, Arthur JSC. CREB phosphorylation at Ser133 regulates transcription via distinct mechanisms downstream of cAMP and MAPK signalling. Biochemical Journal. 2014;458(3):469-79.
284. Sharma D, Parameswaran N. Multifaceted role of β-arrestins in inflammation and disease. Genes & Immunity. 2015;16(8):499-513.
285. Shenoy SK, Drake MT, Nelson CD, Houtz DA, Xiao K, Madabushi S, et al. β-Arrestin-dependent, G protein-independent ERK1/2 activation by the β2 adrenergic receptor. Journal of Biological Chemistry. 2006;281(2):1261-73.
286. Gao H, Sun Y, Wu Y, Luan B, Wang Y, Qu B, et al. Identification of β-arrestin2 as a G protein-coupled receptor-stimulated regulator of NF-κB pathways. Molecular cell. 2004;14(3):303-17.
287. Balasubramani A, Shibata Y, Crawford GE, Baldwin AS, Hatton RD, Weaver CT. Modular utilization of distal cis-regulatory elements controls Ifng gene expression in T cells activated by distinct stimuli. Immunity. 2010;33(1):35-47.
288. Ruan Q, Kameswaran V, Zhang Y, Zheng S, Sun J, Wang J, et al. The Th17 immune response is controlled by the Rel–RORγ–RORγT transcriptional axis. Journal of Experimental Medicine. 2011;208(11):2321-33.
289. Sanders VM, Kasprowicz DJ, Kohm AP, Swanson MA. Neurotransmitter receptors on lymphocytes and other lymphoid cells. Psychoneuroimmunology. 2001;1:161-96.
290. Pawlak M, Ho AW, Kuchroo VK. Cytokines and transcription factors in the differentiation of CD4+ T helper cell subsets and induction of tissue inflammation and autoimmunity. Current opinion in immunology. 2020;67:57-67.
291. Kima JWYB, Junga JBS, Hana JPM, Baeka S-K, Kima TH. Regulation of T Helper Cell Type 2 Immune Response by Controlling Beta-2 Adrenergic Receptor in Dendritic Cells of Patients with Allergic Rhinitis. Int Arch Allergy Immunol. 2023;184:1173-83.
292. Gonczi CMC, Hajiaghayi M, Gholizadeh F, Soares MAX, Touma F, Naranjo CL, et al. The β2-adrenergic receptor agonist terbutaline upregulates T helper-17 cells in a protein kinase A-dependent manner. Human immunology. 2023;84(10):515-24.
293. Diego LM, Jazmin FM, Diana RH, German‐Isauro GF, Salvador FC, Maria‐Elena HC. Modulation of TNF‐α, interleukin‐6, and interleukin‐10 by nebivolol–valsartan and nebivolol–lisinopril polytherapy in SHR rats. Pharmacology Research & Perspectives. 2024;12(2):e1189.
294. Yang S-P, Ho L-J, Lin Y-L, Cheng S-M, Tsao T-P, Chang D-M, et al. Carvedilol, a new antioxidative β-blocker, blocks in vitro human peripheral blood T cell activation by downregulating NF-κB activity. Cardiovascular research. 2003;59(3):776-87.
295. Veverka A, L Salinas J. Nebivolol in the treatment of chronic heart failure. Vascular health and risk management. 2007;3(5):647-54.
296. Zhang Z, Ding L, Jin Z, Gao G, Li H, Zhang L, et al. Nebivolol protects against myocardial infarction injury via stimulation of beta 3-adrenergic receptors and nitric oxide signaling. PLoS One. 2014;9(5):e98179.
297. Van de Water A, Janssens W, Van Neuten J, Xhonneux R, De Cree J, Verhaegen H, et al. Pharmacological and hemodynamic profile of nebivolol, a chemically novel, potent, and selective beta 1-adrenergic antagonist. Journal of cardiovascular pharmacology. 1988;11(5):552-63.
298. Brixius K, Bundkirchen A, Bölck B, Mehlhorn U, Schwinger RH. Nebivolol, bucindolol, metoprolol and carvedilol are devoid of intrinsic sympathomimetic activity in human myocardium. British journal of pharmacology. 2001;133(8):1330-8.
299. Little SR, Leung Z, Quach AB, Hirukawa A, Gholizadeh F, Hajiaghayi M, et al. A Tri‐Droplet Liquid Structure for Highly Efficient Intracellular Delivery in Primary Mammalian Cells Using Digital Microfluidics. Advanced Materials Technologies. 2023;8(21):2300719.
300. Schumann K, Lin S, Boyer E, Simeonov DR, Subramaniam M, Gate RE, et al. Generation of knock-in primary human T cells using Cas9 ribonucleoproteins. Proceedings of the National Academy of Sciences. 2015;112(33):10437-42.
301. Phillips T. Regulation of transcription and gene expression in eukaryotes. Nature Education. 2008;1(1):199.
302. Mason RP, Kubant R, Jacob RF, Walter MF, Boychuk B, Malinski T. Effect of nebivolol on endothelial nitric oxide and peroxynitrite release in hypertensive animals: role of antioxidant activity. Journal of cardiovascular pharmacology. 2006;48(1):862-9.
303. Roth TL, Puig-Saus C, Yu R, Shifrut E, Carnevale J, Li PJ, et al. Reprogramming human T cell function and specificity with non-viral genome targeting. Nature. 2018;559(7714):405-9.
304. Danner S, Frank M, Lohse MJ. Agonist regulation of human β2-adrenergic receptor mRNA stability occurs via a specific AU-rich element. Journal of Biological Chemistry. 1998;273(6):3223-9.
305. Mayati A, Podechard N, Rineau M, Sparfel L, Lagadic-Gossmann D, Fardel O, et al. Benzo (a) pyrene triggers desensitization of β2-adrenergic pathway. Scientific reports. 2017;7(1):3262.
306. Penela P, Ribas C, Mayor Jr F. Mechanisms of regulation of the expression and function of G protein-coupled receptor kinases. Cellular signalling. 2003;15(11):973-81.
307. Kong Y, Ruan L, Qian L, Liu X, Le Y. Norepinephrine promotes microglia to uptake and degrade amyloid β peptide through upregulation of mouse formyl peptide receptor 2 and induction of insulin-degrading enzyme. Journal of Neuroscience. 2010;30(35):11848-57.
308. Kohm AP, Mozaffarian A, Sanders VM. B cell receptor-and β2-adrenergic receptor-induced regulation of B7-2 (CD86) expression in B cells. The Journal of Immunology. 2002;168(12):6314-22.
309. Singh A, Ranjan A. Adrenergic receptor signaling regulates the CD40-receptor mediated anti-tumor immunity. Frontiers in Immunology. 2023;14:1141712.
310. Azzi M, Charest PG, Angers S, Rousseau G, Kohout T, Bouvier M, et al. β-Arrestin-mediated activation of MAPK by inverse agonists reveals distinct active conformations for G protein-coupled receptors. Proceedings of the National Academy of Sciences. 2003;100(20):11406-11.
311. Michel MC, Charlton SJ. Biased agonism in drug discovery—is it too soon to choose a path? Molecular pharmacology. 2018;93(4):259-65.
312. Sanaee F, Jamali F. Action and disposition of the β3-agonist nebivolol in the presence of inflammation; an alternative to conventional β1-blockers. Current Pharmaceutical Design. 2014;20(9):1311-7.
313. Mahdi ZA, Hussain AM, Alblesh HA. Histopathological and Immunological Effects of Nebivolol 5% Topical Cream in Mice Model of Imiquimod-Induced Psoriasis. Al-Rafidain Journal of Medical Sciences (ISSN 2789-3219). 2024;6(1):133-41.
314. McGeachy MJ, Cua DJ, Gaffen SL. The IL-17 family of cytokines in health and disease. Immunity. 2019;50(4):892-906.
315. Paroni M, Maltese V, De Simone M, Ranzani V, Larghi P, Fenoglio C, et al. Recognition of viral and self-antigens by TH1 and TH1/TH17 central memory cells in patients with multiple sclerosis reveals distinct roles in immune surveillance and relapses. Journal of Allergy and Clinical Immunology. 2017;140(3):797-808.
316. Zhao J, Chen X, Herjan T, Li X. The role of interleukin-17 in tumor development and progression. Journal of Experimental Medicine. 2019;217(1):e20190297.
317. Zhao H, Wu L, Yan G, Chen Y, Zhou M, Wu Y, et al. Inflammation and tumor progression: signaling pathways and targeted intervention. Signal transduction and targeted therapy. 2021;6(1):263.
318. Wherry EJ, Kurachi M. Molecular and cellular insights into T cell exhaustion. Nature reviews immunology. 2015;15(8):486-99.
319. Shibutani M, Maeda K, Nagahara H, Fukuoka T, Nakao S, Matsutani S, et al. The prognostic significance of the tumor-infiltrating programmed cell death-1+ to CD8+ lymphocyte ratio in patients with colorectal cancer. Anticancer Research. 2017;37(8):4165-72.
320. Okadome K, Baba Y, Yagi T, Kiyozumi Y, Ishimoto T, Iwatsuki M, et al. Prognostic nutritional index, tumor-infiltrating lymphocytes, and prognosis in patients with esophageal cancer. Annals of Surgery. 2020;271(4):693-700.
321. Wherry EJ. T cell exhaustion. Nature immunology. 2011;12(6):492-9.
322. Barber DL, Wherry EJ, Masopust D, Zhu B, Allison JP, Sharpe AH, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682-7.
323. Urbani S, Amadei B, Tola D, Massari M, Schivazappa S, Missale G, et al. PD-1 expression in acute hepatitis C virus (HCV) infection is associated with HCV-specific CD8 exhaustion. Journal of virology. 2006;80(22):11398-403.
324. Ahmadzadeh M, Johnson LA, Heemskerk B, Wunderlich JR, Dudley ME, White DE, et al. Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood, The Journal of the American Society of Hematology. 2009;114(8):1537-44.
325. Reolo MJ, Otsuka M, Seow JJW, Lee J, Lee YH, Nguyen PH, et al. CD38 marks the exhausted CD8+ tissue-resident memory T cells in hepatocellular carcinoma. Frontiers in Immunology. 2023;14:1182016.
326. Fuller MJ, Zajac AJ. Ablation of CD8 and CD4 T cell responses by high viral loads. The Journal of Immunology. 2003;170(1):477-86.
327. Fuller MJ, Khanolkar A, Tebo AE, Zajac AJ. Maintenance, loss, and resurgence of T cell responses during acute, protracted, and chronic viral infections. The Journal of Immunology. 2004;172(7):4204-14.
328. Ikeda H. Cancer immunotherapy in progress—an overview of the past 130 years. International Immunology. 2025:dxaf002.
329. Tietscher S, Wagner J, Anzeneder T, Langwieder C, Rees M, Sobottka B, et al. A comprehensive single-cell map of T cell exhaustion-associated immune environments in human breast cancer. Nature communications. 2023;14(1):98.
330. Comşa Ş, Cimpean AM, Raica M. The story of MCF-7 breast cancer cell line: 40 years of experience in research. Anticancer research. 2015;35(6):3147-54.
331. Kurozumi S, Kaira K, Matsumoto H, Hirakata T, Yokobori T, Inoue K, et al. β 2-Adrenergic receptor expression is associated with biomarkers of tumor immunity and predicts poor prognosis in estrogen receptor-negative breast cancer. Breast cancer research and treatment. 2019;177:603-10.
332. Qin J-f, Jin F-j, Li N, Guan H-t, Lan L, Ni H, et al. Adrenergic receptor β2 activation by stress promotes breast cancer progression through macrophages M2 polarization in tumor microenvironment. BMB reports. 2015;48(5):295.
333. Magnon C, Hall SJ, Lin J, Xue X, Gerber L, Freedland SJ, et al. Autonomic nerve development contributes to prostate cancer progression. Science. 2013;341(6142):1236361.
334. Kim-Fuchs C, Le CP, Pimentel MA, Shackleford D, Ferrari D, Angst E, et al. Chronic stress accelerates pancreatic cancer growth and invasion: a critical role for beta-adrenergic signaling in the pancreatic microenvironment. Brain, behavior, and immunity. 2014;40:40-7.
335. Hajiaghayi M, Gholizadeh F, Han E, Little SR, Rahbari N, Ardila I, et al. The β2-adrenergic biased agonist nebivolol inhibits the development of Th17 and the response of memory Th17 cells in an NF-κB-dependent manner. Frontiers in Immunology. 2024;15:1446424.
336. Hayata K, Iwahashi M, Ojima T, Katsuda M, Iida T, Nakamori M, et al. Inhibition of IL-17A in tumor microenvironment augments cytotoxicity of tumor-infiltrating lymphocytes in tumor-bearing mice. PLoS One. 2013;8(1):e53131.
337. Corselli M, Saksena S, Nakamoto M, Lomas III WE, Taylor I, Chattopadhyay PK. Single cell multiomic analysis of T cell exhaustion in vitro. Cytometry Part A. 2022;101(1):27-44.
338. Dunsford LS, Thoirs RH, Rathbone E, Patakas A. A human in vitro T cell exhaustion model for assessing immuno-oncology therapies. Immuno-oncology: cellular and translational approaches. 2020:89-101.
339. Wu JE, Manne S, Ngiow SF, Baxter AE, Huang H, Freilich E, et al. In vitro modeling of CD8+ T cell exhaustion enables CRISPR screening to reveal a role for BHLHE40. Science Immunology. 2023;8(86):eade3369.
340. Agnellini P, Wolint P, Rehr M, Cahenzli J, Karrer U, Oxenius A. Impaired NFAT nuclear translocation results in split exhaustion of virus-specific CD8+ T cell functions during chronic viral infection. Proceedings of the National Academy of Sciences. 2007;104(11):4565-70.
341. Egelston CA, Guo W, Tan J, Avalos C, Simons DL, Lim MH, et al. Tumor-infiltrating exhausted CD8+ T cells dictate reduced survival in premenopausal estrogen receptor–positive breast cancer. JCI insight. 2022;7(3):e153963.
342. Li H, van der Leun AM, Yofe I, Lubling Y, Gelbard-Solodkin D, van Akkooi AC, et al. Dysfunctional CD8 T cells form a proliferative, dynamically regulated compartment within human melanoma. Cell. 2019;176(4):775-89. e18.
343. Utzschneider DT, Alfei F, Roelli P, Barras D, Chennupati V, Darbre S, et al. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. Journal of Experimental Medicine. 2016;213(9):1819-34.
344. Bucks CM, Norton JA, Boesteanu AC, Mueller YM, Katsikis PD. Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. The Journal of Immunology. 2009;182(11):6697-708.
345. Selli ME, Landmann JH, Arveseth C, Singh N. Inducing T cell dysfunction by chronic stimulation of CAR-engineered T cells targeting cancer cells in suspension cultures. STAR protocols. 2023;4(1):101954.
346. Vardhana SA, Hwee MA, Berisa M, Wells DK, Yost KE, King B, et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nature immunology. 2020;21(9):1022-33.
347. Qiao G, Chen M, Bucsek MJ, Repasky EA, Hylander BL. Adrenergic signaling: a targetable checkpoint limiting development of the antitumor immune response. Frontiers in immunology. 2018;9:164.
348. Eng JW-L, Kokolus KM, Reed CB, Hylander BL, Ma WW, Repasky EA. A nervous tumor microenvironment: the impact of adrenergic stress on cancer cells, immunosuppression, and immunotherapeutic response. Cancer Immunology, Immunotherapy. 2014;63:1115-28.
349. Johnson M. Molecular mechanisms of β2-adrenergic receptor function, response, and regulation. Journal of Allergy and Clinical Immunology. 2006;117(1):18-24.
350. Wu VH, Yung BS, Faraji F, Saddawi-Konefka R, Wang Z, Wenzel AT, et al. The GPCR–Gαs–PKA signaling axis promotes T cell dysfunction and cancer immunotherapy failure. Nature immunology. 2023;24(8):1318-30.
All items in Spectrum are protected by copyright, with all rights reserved. The use of items is governed by Spectrum's terms of access.

Repository Staff Only: item control page

Downloads per month over past year

Research related to the current document (at the CORE website)
- Research related to the current document (at the CORE website)
Back to top Back to top