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

Shirdi E. Schmiel, Lokesh A. Kalekar, Na Zhang, Thomas W. Blankespoor, Londyn J. Robinson, Daniel L Mueller

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)773-783
Number of pages11
JournalArthritis and Rheumatology
Volume71
Issue number5
DOIs
StatePublished - May 1 2019

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Purinergic P1 Receptors
Helper-Inducer T-Lymphocytes
Germinal Center
Glucose-6-Phosphate Isomerase
Arthritis
T-Lymphocytes
Immunoglobulin G
Cell Lineage
Cell Differentiation
Autoantigens
Serum
Autoantibodies
Disease Progression
B-Lymphocytes
Cell Count
Phosphates
Phenotype
Antigens
Therapeutics

PubMed: MeSH publication types

  • Journal Article

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Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells. / Schmiel, Shirdi E.; Kalekar, Lokesh A.; Zhang, Na; Blankespoor, Thomas W.; Robinson, Londyn J.; Mueller, Daniel L.

In: Arthritis and Rheumatology, Vol. 71, No. 5, 01.05.2019, p. 773-783.

Research output: Contribution to journalArticle

Schmiel, Shirdi E. ; Kalekar, Lokesh A. ; Zhang, Na ; Blankespoor, Thomas W. ; Robinson, Londyn J. ; Mueller, Daniel L. / Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center–Follicular Helper T Cells. In: Arthritis and Rheumatology. 2019 ; Vol. 71, No. 5. pp. 773-783.
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abstract = "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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AU - Robinson, Londyn J.

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