AIMS/HYPOTHESIS Type 1 diabetes is an autoimmune disorder characterised by loss of insulin-producing beta cells of the pancreas. Progress in understanding the cellular and molecular mechanisms underlying the human disease has been hampered by a dearth of appropriate human experimental models. We previously reported the characterisation of islet-infiltrating CD4+ T cells from a deceased organ donor who had type 1 diabetes. METHODS Induced pluripotent stem cell (iPSC) lines derived from the above donor were differentiated into CD14+ macrophages and tested for their capacity to present antigen to T cell receptors (TCRs) derived from islet-infiltrating CD4+ T cells from the same donor. RESULTS The iPSC macrophages displayed typical macrophage morphology, surface markers (CD14, CD86, CD16 and CD11b) and were phagocytic. In response to IFNγ treatment, iPSC macrophages upregulated expression of HLA class II, a characteristic that correlated with their capacity to present epitopes derived from proinsulin C-peptide to a T cell line expressing TCRs derived from islet-infiltrating CD4+ T cells of the original donor. T cell activation was specifically blocked by anti-HLA-DQ antibodies but not by antibodies directed against HLA-DR. CONCLUSIONS/INTERPRETATION This study provides a proof of principle for the use of iPSC-derived immune cells for modelling key cellular interactions in human type 1 diabetes.

中文翻译：

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诱导型多能干细胞巨噬细胞向1型糖尿病供体匹配的胰岛浸润性T细胞中的胰岛素原特异性T细胞受体呈递抗原。

目的/假设1型糖尿病是一种自身免疫性疾病，其特征是胰腺的胰岛素生成β细胞丢失。由于缺乏合适的人类实验模型，阻碍了人们理解人类疾病的细胞和分子机制的进展。我们先前曾报道过来自死者的1型糖尿病器官供体的胰岛浸润CD4 + T细胞的特征。方法将上述供体衍生的诱导多能干细胞（iPSC）分化为CD14 +巨噬细胞，并测试其向来自同一供体的胰岛浸润CD4 + T细胞衍生的T细胞受体（TCR）呈递抗原的能力。结果iPSC巨噬细胞表现出典型的巨噬细胞形态，表面标记（CD14，CD86，CD16和CD11b），并且具有吞噬功能。对IFNγ的治疗，iPSC巨噬细胞上调了HLA II类的表达，这一特性与其将来自胰岛素原C肽的抗原决定簇呈递到表达TCR的T细胞系的能力有关，所述TCR来源于原始供体的胰岛浸润CD4 + T细胞。T细胞活化被抗HLA-DQ抗体特异性阻断，但未被抗HLA-DR的抗体阻断。结论/解释这项研究提供了使用iPSC衍生的免疫细胞模拟人1型糖尿病关键细胞相互作用的原理证明。T细胞活化被抗HLA-DQ抗体特异性阻断，但未被抗HLA-DR的抗体阻断。结论/解释这项研究提供了使用iPSC衍生的免疫细胞模拟人1型糖尿病关键细胞相互作用的原理证明。T细胞活化被抗HLA-DQ抗体特异性阻断，但未被抗HLA-DR的抗体阻断。结论/解释这项研究提供了使用iPSC衍生的免疫细胞模拟人1型糖尿病关键细胞相互作用的原理证明。