Abstract
Type 1 diabetes mellitus (T1D) is an immune-mediated disease. The autoreactive T cells in T1D patients attack and destroy their own pancreatic cells. In order to systematically investigate the potential autoreactive T cell receptors (TCRs), we used a high-throughput immune repertoire sequencing technique to profile the spectrum of TCRs in individual T1D patients and controls. We sequenced the T cell repertoire of nine T1D patients, four type 2 diabetes (T2D) patients, and six nondiabetic controls. The diversity of the T cell repertoire in T1D patients was significantly decreased in comparison with T2D patients (P=7.0E−08 for CD4+ T cells, P=1.4E−04 for CD8+ T cells) and nondiabetic controls (P=2.7E−09 for CD4+ T cells, P=7.6E−06 for CD8+ T cells). Moreover, T1D patients had significantly more highly-expanded T cell clones than T2D patients (P=5.2E−06 for CD4+ T cells, P=1.9E−07 for CD8+ T cells) and nondiabetic controls (P=1.7E−07 for CD4+ T cells, P=3.3E−03 for CD8+ T cells). Furthermore, we identified a group of highly-expanded T cell receptor clones that are shared by more than two T1D patients. Although further validation in larger cohorts is needed, our data suggest that T cell receptor diversity measurements may become a valuable tool in investigating diabetes, such as using the diversity as an index to distinguish different types of diabetes.
Highlights
Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by infiltration of leukocytes into the islets of the pancreas, resulting in progressive pancreatic b-cell destruction and loss of insulin production [1,2,3]
Considering T cell receptors (TCRs) and human leukocyte antigen (HLA) are closely related, we investigated HLA genotyping in some T1D patients
Sequencing reads were aligned against the reference sequences of genes encoding human T cell receptor beta variable (TRBV), diversity (TRBD), and joining (TRBJ) [29]
Summary
Type 1 diabetes mellitus (T1D) is an autoimmune disease characterized by infiltration of leukocytes into the islets of the pancreas, resulting in progressive pancreatic b-cell destruction and loss of insulin production [1,2,3]. The most direct evidence of the pathogenic role of T cells in T1D is from the biobreeding rat and the nonobese diabetic (NOD) mouse models [8,9]. Extensive studies in mouse models have demonstrated that T cells play crucial roles in the pathogenesis of T1D, as the disease can be transferred by T cell clones or a heterogeneous T cell population [10,11,12]. Wicker et al transferred splenocytes of NOD mice to young mice. These recipient mice develop diabetic at a higher frequency and at a younger age than their controls [10]. CD4+ T cells mostly recognize insulin and are the main cellular effectors, whereas CD8+ cytotoxic T cells recognize peptide epitopes presented on the b cell surface and directly contribute to b cell death [13,14]
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