Key Points T cells or whole spleen from NOD-PerIg mice transfer neuritis to NOD.scid recipients. CD4+ T cells are necessary and sufficient to transfer neuritis. Islet and sciatic nerve CD4+ T cells have differing patterns of CD95, PD-1, and Tim-3. It has become increasingly appreciated that autoimmune responses against neuronal components play an important role in type 1 diabetes (T1D) pathogenesis. In fact, a large proportion of islet-infiltrating B lymphocytes in the NOD mouse model of T1D produce Abs directed against the neuronal type III intermediate filament protein peripherin. NOD-PerIg mice are a previously developed BCR-transgenic model in which virtually all B lymphocytes express the H and L chain Ig molecules from the intra-islet–derived anti-peripherin–reactive hybridoma H280. NOD-PerIg mice have accelerated T1D development, and PerIg B lymphocytes actively proliferate within islets and expand cognitively interactive pathogenic T cells from a pool of naive precursors. We now report adoptively transferred T cells or whole splenocytes from NOD-PerIg mice expectedly induce T1D in NOD.scid recipients but, depending on the kinetics of disease development, can also elicit a peripheral neuritis (with secondary myositis). This neuritis was predominantly composed of CD4+ and CD8+ T cells. Ab depletion studies showed neuritis still developed in the absence of NOD-PerIg CD8+ T cells but required CD4+ T cells. Surprisingly, sciatic nerve–infiltrating CD4+ cells had an expansion of IFN-γ− and TNF-α− double-negative cells compared with those within both islets and spleen. Nerve and islet-infiltrating CD4+ T cells also differed by expression patterns of CD95, PD-1, and Tim-3. Further studies found transitory early B lymphocyte depletion delayed T1D onset in a portion of NOD-PerIg mice, allowing them to survive long enough to develop neuritis outside of the transfer setting. Together, this study presents a new model of peripherin-reactive B lymphocyte–dependent autoimmune neuritis.

中文翻译：

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NOD-PerIg 小鼠的 T 细胞同时靶向胰腺和神经组织

关键点来自 NOD-PerIg 小鼠的 T 细胞或整个脾脏将神经炎转移到 NOD.scid 受体。CD4+ T 细胞是转移神经炎所必需且足够的。胰岛和坐骨神经 CD4+ T 细胞具有不同的 CD95、PD-1 和 Tim-3 模式。人们越来越认识到，针对神经元成分的自身免疫反应在 1 型糖尿病 (T1D) 发病机制中起着重要作用。事实上，在 T1D 的 NOD 小鼠模型中，大部分胰岛浸润 B 淋巴细胞产生针对神经元 III 型中间丝蛋白外周蛋白的抗体。NOD-PerIg 小鼠是先前开发的 BCR 转基因模型，其中几乎所有 B 淋巴细胞都表达来自胰岛内衍生的抗外周蛋白反应性杂交瘤 H280 的 H 和 L 链 Ig 分子。NOD-PerIg 小鼠加速了 T1D 的发展，和 PerIg B 淋巴细胞在胰岛内积极增殖，并从原始前体池中扩增具有认知相互作用的致病性 T 细胞。我们现在报告过继转移的 T 细胞或来自 NOD-PerIg 小鼠的全脾细胞，预期在 NOD.scid 受体中诱导 T1D，但根据疾病发展的动力学，也可能引发周围神经炎（伴有继发性肌炎）。这种神经炎主要由 CD4+ 和 CD8+ T 细胞组成。Ab 耗竭研究表明，在没有 NOD-PerIg CD8+ T 细胞但需要 CD4+ T 细胞的情况下，神经炎仍会发生。令人惊讶的是，与胰岛和脾脏内的细胞相比，坐骨神经浸润的 CD4+ 细胞具有 IFN-γ- 和 TNF-α- 双阴性细胞的扩增。神经和胰岛浸润 CD4+ T 细胞也因 CD95、PD-1 和 Tim-3 的表达模式而异。进一步的研究发现，在一部分 NOD-PerIg 小鼠中，短暂的早期 B 淋巴细胞耗竭延迟了 T1D 的发病，使它们能够存活足够长的时间以在转移环境之外发展为神经炎。总之，这项研究提出了一种新的外周蛋白反应性 B 淋巴细胞依赖性自身免疫性神经炎模型。