Key Points Unlike autoimmune arthritis, insulitis and T1D develop without SAP. B cell Ag presentation can drive SAP-deficient T cell proliferation. SAP−/− NOD mice show intact IFN-γ responses and TFH1 cell pancreatic infiltration. Visual Abstract 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 SAP in the autoantibody-mediated K/BxN model, organized insulitis and diabetes onset were unabated, despite a blocked anti-insulin vaccine response in SAP-deficient NOD mice. GC Tfh and GC B cell development were blocked by loss of SAP in K/BxN mice. In contrast, although GC B cell formation was markedly reduced in SAP-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 SAP. NOD T cells override SAP 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 SAP 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 SAP.

中文翻译：

---

T-B 淋巴细胞相互作用促进 1 型糖尿病的发生，与 SLAM 相关蛋白无关

要点 与自身免疫性关节炎不同，胰岛炎和 T1D 在没有 SAP 的情况下发展。B 细胞抗原呈递可以驱动 SAP 缺陷型 T 细胞增殖。SAP-/- NOD 小鼠显示完整的 IFN-γ 反应和 TFH1 细胞胰腺浸润。视觉摘要信号淋巴细胞活化分子相关蛋白 (SAP) 是 T-B 淋巴细胞相互作用的关键细胞内信号分子，可驱动生发中心 (GC) 中的 T 滤泡辅助 (Tfh) 细胞发育。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。这种悖论表明 Tfh 细胞是关键的病理效应物，与 T1D 中观察到的 Tfh 特征一致。为了了解完全发育的 Tfh (GC Tfh) 如何促进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。尽管自发性关节炎在自身抗体介导的 K/BxN 模型中依赖于 SAP，但有组织的胰岛炎和糖尿病发作有增无减，尽管 SAP 缺陷型 NOD 小鼠的抗胰岛素疫苗反应受阻。GC Tfh 和 GC B 细胞发育被 K/BxN 小鼠中 SAP 的丧失所阻断。相比之下，尽管 SAP 缺陷型 NOD 小鼠的 GC B 细胞形成显着减少，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) 亚群偏倚，SAP 缺失增强了这种偏倚。NOD T 细胞超越 SAP 要求以响应 Ag 呈现进行激活和增殖，证明了在 T1D 易感小鼠中产生生产性同源 T-B 淋巴细胞相互作用的潜力。我们发现当自身抗体驱动的免疫复合物促进炎症但不是有效的器官特异性自身免疫攻击所必需时，SAP 是必不可少的。因此，在经典 GC 反应中诱导的 Tfh 对于 T1D 是可有可无的，但 NOD 模型中的自身免疫过程保留了没有 SAP 的致病性 Tfh。