The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center

Abbott, Robert G.; Silva, Murillo; Labuda, Jasmine C.; Thayer, Molly; Cain, Derek W.; Philbrook, Phaethon; Sethumadhavan, Shalini; Hatfield, Stephen; Ohta, Akio; Sitkovsky, Michail V.

doi:10.1074/jbc.c116.764043

Cited by 26 publications

(19 citation statements)

References 41 publications

(40 reference statements)

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“…These observations are consistent with other studies that demonstrated that NP-specific switched memory cells characteristically expressed CD73 [71]. CD11c+ T-bet+ IgM memory cells also exhibit relatively high expression of Adora2a , which encodes a G protein-coupled adenosine receptor of the A2A subtype [72, 73]. Adenosine has been reported to exhibit anti-inflammatory activity [74].…”

Section: Transcriptome Analysessupporting

confidence: 90%

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

Winslow

Papillion

Kenderes

et al. 2017

Cellular Immunology

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CD11c+ T-bet+ B cells have now been detected and characterized in different experimental and clinical settings, in both mice and humans. Whether such cells are monolithic, or define subsets of B cells with different functions is not yet known. Our studies have identified CD11c+ IgM+ CD19hi splenic IgM memory B cells that appear at approximately three weeks post-ehrlichial infection, and persist indefinitely, during low-level chronic ehrlichial infection. Although the CD11c+T-bet+ B cells we have described are distinct, they appear to share many features with similar cells detected under diverse conditions, including viral infections, aging, and autoimmunity. We propose that CD11c+ T-bet+ B cells as a group share characteristics of memory B cells that are maintained under conditions of inflammation and/or low-level chronic antigen stimulation. In some cases, these cells may be advantageous, by providing immunity to re-infection, but in others may be deleterious, by contributing to aged-associated autoimmune responses.

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Section: Transcriptome Analysessupporting

confidence: 90%

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

Winslow

Papillion

Kenderes

et al. 2017

Cellular Immunology

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“…Alternative roles of the A2AR include reducing T cell motility through the modulation of potassium channels [147], regulation of metabolism, and modulation of memory differentiation through PI3K-AKT pathways [9,122,144,[148][149][150]. Although A2AR and A2BR are more highly expressed in effector memory cells their activation is associated with the preservation of a naïve/ central memory phenotype [35].…”

Section: Effect Of Adenosine On T Cell Responsesmentioning

confidence: 99%

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Sek¹,

Mølck²,

Stewart³

et al. 2018

Preprint

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The immune system plays a major role in the surveillance and control of malignant cells, with the presence of tumor infiltrating lymphocytes (TILs) correlating with better patient prognosis in multiple tumor types. The development of ‘checkpoint blockade’ and adoptive cellular therapy has revolutionized the landscape of cancer treatment and highlights the potential of utilizing the patient’s own immune system to eradicate cancer. One mechanism of tumor-mediated immunosuppression that has gained attention as a potential therapeutic target is the purinergic signaling axis, whereby the production of the purine nucleoside adenosine in the tumor microenvironment can potently suppress T and NK cell function. The production of extracellular adenosine is mediated by the cell surface ectoenzymes CD73, CD39 and CD38 and therapeutic agents have been developed to target these as well as the downstream adenosine receptors (A1R, A2AR, A2BR, A3R) to enhance anti-tumor immune responses. This review will discuss the role of adenosine and adenosine receptor signaling in tumor and immune cells with a focus on their cell-specific function and their potential as targets in cancer immunotherapy.

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“…Investigations in our laboratory and others have recently determined that A2aR signaling during the primary response to a foreign antigen in strong adjuvant has the ability to divert CD4 T cell differentiation away from the follicular helper T (Tfh) and germinal center (GC)–Tfh cell lineages, and consequently could reduce help for the differentiation of antigen‐specific GC B cells and isotype class–switched plasmablasts . In RA, autoreactive B cells are thought to be induced by Tfh cells to undergo clonal expansion, isotype class–switch recombination, and somatic hypermutation within the GCs, and this ultimately leads to the differentiation of anti–citrullinated protein antibody–secreting plasma cells .…”

Section: Introductionmentioning

confidence: 99%

Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells

Schmiel

Kalekar

Zhang

et al. 2019

Arthritis & Rheumatology

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Objective. CD4 germinal center (GC)-follicular helper T (Tfh) cells are important in the pathogenesis of autoimmune arthritis. Previous studies have shown that adenosine 2a receptor (A2aR; Adora2a) signaling can divert CD4 T cells away from the GC-Tfh cell lineage during the primary response to foreign antigens. This study was undertaken to examine the effects of A2aR signaling on CD4 T cells during the recognition of self antigen in a murine model of autoimmune arthritis.Methods. Wild-type and Adora2a-deficient mouse KRN T cell receptor-transgenic CD4 T cells specific for glucose-6-phosphate isomerase (GPI)/I-A g7 were transferred into immunodeficient Tcra −/− I-A g7 -expressing mice to induce arthritis. Recipients were then treated with either the selective A2aR agonist CGS-21680 (CGS) or phosphate buffered saline alone. Severity of disease, autoantibody titers, KRN T cell numbers and phenotype, and GPI-specific isotype class-switched plasmablasts were tracked.Results. CGS treatment inhibited the development of arthritis and differentiation of KRN GC-Tfh cells, blocked the appearance of high-affinity GPI-specific and IgG1 isotype class-switched polyclonal plasmablasts, and led to a reduction in serum titers of anti-GPI IgG1. In addition, therapeutic administration of CGS after the onset of arthritis blocked further disease progression in association with reductions in the number of KRN GC-Tfh cells and anti-GPI IgG1 serum titers.Conclusion. Strong A2aR signaling diverts autoreactive CD4 T cell differentiation away from the GC-Tfh cell lineage, thus reducing help for the differentiation of dangerous autoreactive B cells that promote arthritis. These data in a mouse model of autoimmune arthritis suggest that A2aR and its downstream signaling pathways in CD4 T cells may be promising therapeutic targets for interfering with potentially dangerous autoreactive GC-Tfh cell differentiation.

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The GS Protein-coupled A2a Adenosine Receptor Controls T Cell Help in the Germinal Center

Cited by 26 publications

References 41 publications

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

CD11c+ T-bet+ memory B cells: Immune maintenance during chronic infection and inflammation?

Targeting Adenosine Receptor Signaling in Cancer Immunotherapy

Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells

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