PDF(Pubmed)
Abstract：
Human type 1 diabetes (T1D) is caused by autoimmune attack on the insulin-producing pancreatic beta cells by islet antigen-reactive T cells. How human islet antigen-reactive (IAR) CD4+ memory T cells from peripheral blood affect T1D progression in the pancreas is poorly understood. Here, we aim to determine if IAR T cells in blood could be detected in pancreas. We identify paired αβ (TRA/TRB) T cell receptors (TCRs) in IAR T cells from the blood of healthy, at-risk, new-onset, and established T1D donors, and measured sequence overlap with TCRs in pancreata from healthy, at risk and T1D organ donors. We report extensive TRA junction sharing between IAR T cells and pancreas-infiltrating T cells (PIT), with perfect-match or single-mismatch TRA junction amino acid sequences comprising ~29% total unique IAR TRA junctions (942/3,264). PIT-matched TRA junctions were largely public and enriched for TRAV41 usage, showing significant nucleotide sequence convergence, increased use of germline-encoded versus non-templated residues in epitope engagement, and a potential for cross-reactivity. Our findings thus link T cells with distinctive germline-like TRA chains in the peripheral blood with T cells in the pancreas.
摘要：
人类1型糖尿病（T1D）是由胰岛抗原反应性T细胞对产生胰岛素的胰腺β细胞的自身免疫攻击引起的。来自外周血的人胰岛抗原反应性（IAR）CD4记忆T细胞如何影响胰腺中的T1D进展尚不清楚。这里,我们的目的是确定是否可以在胰腺中检测到血液中的IART细胞.我们从健康的血液中鉴定IART细胞中的成对αβ（TRA/TRB）T细胞受体（TCR），有风险，新发,并建立了T1D捐赠者，和测量的序列与健康胰腺中的TCR重叠，有风险和T1D器官捐献者。我们报告了IART细胞和胰腺浸润T细胞（PIT）之间广泛的TRA连接共享，具有完美匹配或单错配TRA连接氨基酸序列，占〜29％的总独特IARTRA连接（942/3,264）。与PIT匹配的TRA接头在很大程度上是公开的，并且为TRAV41的使用而丰富。显示出显著的核苷酸序列收敛，表位接合中种系编码的残基与非模板化残基的使用增加，和交叉反应的可能性。因此，我们的发现将外周血中具有独特种系样TRA链的T细胞与胰腺中的T细胞联系起来。
