Walker L S K, von Herrath M
Institute of Immunity and Transplantation, University College London Division of Infection and Immunity, Royal Free Campus, London, UK.
Type 1 Diabetes Center, La Jolla Institute for Allergy and Immunology, La Jolla, CA and Novo Nordisk Diabetes Research and Development Center, Seattle, WA, USA.
Clin Exp Immunol. 2016 Jan;183(1):16-29. doi: 10.1111/cei.12672. Epub 2015 Jul 28.
Susceptibility to type 1 diabetes is associated strongly with human leucocyte antigen (HLA) genes, implicating T cells in disease pathogenesis. In humans, CD8 T cells predominantly infiltrate the islets, yet their activation and propagation probably requires CD4 T cell help. CD4 T cells can select from several differentiation fates following activation, and this choice has profound consequences for their subsequent cytokine production and migratory potential. In turn, these features dictate which other immune cell types T cells interact with and influence, thereby determining downstream effector functions. Obtaining an accurate picture of the type of CD4 T cell differentiation associated with a particular immune-mediated disease therefore constitutes an important clue when planning intervention strategies. Early models of T cell differentiation focused on the dichotomy between T helper type 1 (Th1) and Th2 responses, with type 1 diabetes (T1D) being viewed mainly as a Th1-mediated pathology. However, several additional fate choices have emerged in recent years, including Th17 cells and follicular helper T cells. Here we revisit the issue of T cell differentiation in autoimmune diabetes, highlighting new evidence from both mouse models and patient samples. We assess the strengths and the weaknesses of the Th1 paradigm, review the data on interleukin (IL)-17 production in type 1 diabetes and discuss emerging evidence for the roles of IL-21 and follicular helper T cells in this disease setting. A better understanding of the phenotype of CD4 T cells in T1D will undoubtedly inform biomarker development, improve patient stratification and potentially reveal new targets for therapeutic intervention.
1型糖尿病易感性与人类白细胞抗原（HLA）基因密切相关，这表明T细胞参与了疾病的发病机制。在人类中，CD8 T细胞主要浸润胰岛，但其激活和增殖可能需要CD4 T细胞的辅助。激活后，CD4 T细胞可以从几种分化命运中进行选择，而这种选择对其随后的细胞因子产生和迁移潜力具有深远影响。反过来，这些特征决定了T细胞与哪些其他免疫细胞类型相互作用并产生影响，从而决定下游效应功能。因此，准确了解与特定免疫介导疾病相关的CD4 T细胞分化类型，在制定干预策略时是一条重要线索。早期的T细胞分化模型主要关注1型辅助性T细胞（Th1）和2型辅助性T细胞（Th2）反应之间的二分法，1型糖尿病（T1D）主要被视为一种由Th1介导的病理状态。然而，近年来出现了几种额外的命运选择，包括Th17细胞和滤泡辅助性T细胞。在这里，我们重新审视自身免疫性糖尿病中T细胞分化的问题，重点介绍来自小鼠模型和患者样本的新证据。我们评估了Th1范式的优缺点，回顾了1型糖尿病中白细胞介素（IL）-17产生的数据，并讨论了IL-21和滤泡辅助性T细胞在这种疾病背景下作用的新证据。更好地了解T1D中CD4 T细胞的表型无疑将为生物标志物的开发提供信息，改善患者分层，并可能揭示治疗干预的新靶点。
