腺嘌呤 2a 受体信号通过抑制致病生发中心滤泡辅助 T 细胞阻断小鼠自身免疫性关节炎。
Adenosine 2a Receptor Signal Blockade of Murine Autoimmune Arthritis via Inhibition of Pathogenic Germinal Center-Follicular Helper T Cells.
机构信息
University of Minnesota Medical School, Minneapolis.
出版信息
Arthritis Rheumatol. 2019 May;71(5):773-783. doi: 10.1002/art.40796. Epub 2019 Mar 25.
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 were transferred into immunodeficient Tcra I-A -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.
目的
CD4 生发中心（GC）-滤泡辅助 T（Tfh）细胞在自身免疫性关节炎的发病机制中起重要作用。先前的研究表明，腺苷 2a 受体（A2aR；Adora2a）信号可以在对外来抗原的初次应答中使 CD4 T 细胞偏离 GC-Tfh 细胞谱系。本研究旨在研究 A2aR 信号在自身抗原识别过程中对 CD4 T 细胞的影响，建立自身免疫性关节炎的小鼠模型。
方法
将特异性识别葡萄糖-6-磷酸异构酶（GPI）/I-A 的 KRN T 细胞受体转基因 CD4 T 细胞的野生型和 Adora2a 缺陷型小鼠转移到免疫缺陷型 Tcra I-A 表达的小鼠中，以诱导关节炎。然后，用选择性 A2aR 激动剂 CGS-21680（CGS）或磷酸缓冲盐水单独处理受体。跟踪疾病的严重程度、自身抗体滴度、KRN T 细胞数量和表型以及 GPI 特异性同种型转换浆母细胞。
结果
CGS 治疗抑制了关节炎的发展和 KRN GC-Tfh 细胞的分化，阻断了高亲和力 GPI 特异性和 IgG1 同种型转换多克隆浆母细胞的出现，并导致抗 GPI IgG1 血清滴度降低。此外，关节炎发作后给予 CGS 治疗可阻断进一步的疾病进展，同时减少 KRN GC-Tfh 细胞的数量和抗 GPI IgG1 血清滴度。
结论
强烈的 A2aR 信号使自身反应性 CD4 T 细胞分化偏离 GC-Tfh 细胞谱系，从而减少对促进关节炎的危险自身反应性 B 细胞分化的帮助。这些在自身免疫性关节炎小鼠模型中的数据表明，A2aR 及其在 CD4 T 细胞中的下游信号通路可能是干扰潜在危险自身反应性 GC-Tfh 细胞分化的有前途的治疗靶点。
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