Abstract
Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Here we show, by analyzing >2 × 108TCRB sequences of circulating naive, central memory, regulatory and stem cell-like memory CD4+ T cell subsets from patients with type 1 diabetes and healthy donors, that patients have shorter TCRB complementarity-determining region 3s (CDR3), in all cell subsets, introduced by increased deletions/reduced insertions during VDJ rearrangement. High frequency of short CDR3s is also observed in unproductive TCRB sequences, which are not subjected to thymic culling, suggesting that the shorter CDR3s arise independently of positive/negative selection. Moreover, TCRB CDR3 clonotypes expressed by autoantigen-specific CD4+ T cells are shorter compared with anti-viral T cells, and with those from healthy donors. Thus, early events in thymic T cell development and repertoire generation are abnormal in type 1 diabetes, which suggest that short CDR3s increase the potential for self-recognition, conferring heightened risk of autoimmune disease.
Highlights
Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity
The T cell receptor beta chain (TCRB) repertoires of different CD4+ T cell subsets were examined using generation sequencing technology in 14 recently diagnosed patients with type 1 diabetes (T1D) and 14 matched healthy donors (HD) who did not differ in mean age, distribution of gender, mean total cell number, cell subset yield or possession of human leukocyte antigen (HLA)-DRB1*0401 or *0301 haplotypes associated with T1D (Supplementary Table 1; Supplementary Figs. 1a–e and 2a)
There is a considerable gap in knowledge and understanding of the factors beyond those encoded in the germline that predispose to type 1 diabetes (T1D)
Summary
Defects in T cell receptor (TCR) repertoire are proposed to predispose to autoimmunity. Early events in thymic T cell development and repertoire generation are abnormal in type 1 diabetes, which suggest that short CDR3s increase the potential for self-recognition, conferring heightened risk of autoimmune disease. One genetic element that cannot be revealed to be diseaselinked in genome studies, but could have considerable bearing on T1D risk, is the gene loci encoding the antigenreceptors borne by T and B lymphocytes These receptors may confer the property of autoantigen recognition, fundamental bedrock of organ-specific autoimmune disease. Our results demonstrate that TCRBs specific for autoantigens are shorter than their anti-viral counterparts, providing a link between self-reactivity and TCRB CDR3 length These findings implicate abnormal thymic recombination as a predisposing factor for T1D
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