Division of Rheumatology and Immunology, Department of Medicine, Vanderbilt University Medical Center, Nashville, TN 37232;
Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, TN 37232.
J Immunol. 2020 Dec 15;205(12):3263-3276. doi: 10.4049/jimmunol.1900464. Epub 2020 Nov 16.
Signaling lymphocytic activation molecule-associated protein (SAP), a critical intracellular signaling molecule for T-B lymphocyte interactions, drives T follicular helper (Tfh) cell development in germinal centers (GCs). High-affinity islet autoantibodies predict type 1 diabetes (T1D) but do not cause β cell destruction. This paradox intimates Tfh cells as key pathologic effectors, consistent with an observed Tfh signature in T1D. To understand how fully developed Tfh (GC Tfh) contribute to different autoimmune processes, we investigated the role of SAP in T1D and autoantibody-mediated arthritis. Whereas spontaneous arthritis depended on in the autoantibody-mediated K/BxN model, organized insulitis and diabetes onset were unabated, despite a blocked anti-insulin vaccine response in -deficient NOD mice. GC Tfh and GC B cell development were blocked by loss of in K/BxN mice. In contrast, although GC B cell formation was markedly reduced in -deficient NOD mice, T cells with a GC Tfh phenotype were found at disease sites. CXCR3 CCR6 (Tfh1) subset bias was observed among GC Tfh cells infiltrating the pancreas of NOD mice, which was enhanced by loss of NOD T cells override requirement to undergo activation and proliferation in response to Ag presentation, demonstrating the potential for productive cognate T-B lymphocyte interactions in T1D-prone mice. We find that is essential when autoantibody-driven immune complexes promote inflammation but is not required for effective organ-specific autoimmune attack. Thus, Tfh induced in classic GC reactions are dispensable for T1D, but the autoimmune process in the NOD model retains pathogenic Tfh without .
信号淋巴细胞激活分子相关蛋白（SAP）是 T-B 淋巴细胞相互作用的关键细胞内信号分子，它驱动生发中心（GC）中的滤泡辅助性 T 细胞（Tfh）细胞的发育。高亲和力胰岛自身抗体可预测 1 型糖尿病（T1D），但不会导致β细胞破坏。这一悖论暗示 Tfh 细胞是关键的病理性效应细胞，与 T1D 中观察到的 Tfh 特征一致。为了了解完全发育的 Tfh（GC Tfh）如何参与不同的自身免疫过程，我们研究了 SAP 在 T1D 和自身抗体介导的关节炎中的作用。虽然自发性关节炎依赖于 在自身抗体介导的 K/BxN 模型中，尽管在 -缺陷的 NOD 小鼠中阻断了抗胰岛素疫苗反应，但组织性胰岛炎和糖尿病的发作并未减轻。在 K/BxN 小鼠中，SAP 的缺失阻断了 GC Tfh 和 GC B 细胞的发育。相比之下，尽管 -缺陷的 NOD 小鼠中 GC B 细胞的形成明显减少，但在疾病部位发现了具有 GC Tfh 表型的 T 细胞。在浸润 NOD 小鼠胰腺的 GC Tfh 细胞中观察到 CXCR3 CCR6（Tfh1）亚群偏向，这种偏向在 -缺陷的 NOD 小鼠中更为明显。NOD T 细胞在对抗原呈递的反应中不需要 ，就可以进行激活和增殖，这表明在易患 T1D 的小鼠中，T 细胞和 B 细胞之间存在有活性的同源相互作用的潜力。我们发现，当自身抗体驱动的免疫复合物促进炎症时，SAP 是必不可少的，但在 NOD 模型中有效的器官特异性自身免疫攻击并不需要 SAP。因此，在经典 GC 反应中诱导的 Tfh 在 T1D 中是可有可无的，但 NOD 模型中的自身免疫过程保留了致病性 Tfh，而不需要 SAP。
