Abstract
Hybrid Insulin Peptides (HIPs), which consist of insulin fragments fused to other peptides from β-cell secretory granule proteins, are CD4 T cell autoantigens in type 1 diabetes (T1D). We have studied HIPs and HIP-reactive CD4 T cells extensively in the context of the non-obese diabetic (NOD) mouse model of autoimmune diabetes and have shown that CD4 T cells specific for HIPs are major contributors to disease pathogenesis. Additionally, in the human context, HIP-reactive CD4 T cells can be found in the islets and peripheral blood of T1D patients. Here, we performed an in-depth characterization of the CD4 T cell response to a C-peptide/C-peptide HIP (HIP11) in human T1D. We identified the TCR expressed by the previously-reported HIP11-reactive CD4 T cell clone E2, which was isolated from the peripheral blood of a T1D patient, and determined that it recognizes HIP11 in the context of HLA-DQ2. We also identified a HIP11-specific TCR directly in the islets of a T1D donor and demonstrated that this TCR recognizes a different minimal epitope of HIP11 presented by HLA-DQ8. We generated and tested an HLA-DQ2 tetramer loaded with HIP11 that will enable direct ex vivo interrogation of CD4 T cell responses to HIP11 in human patients and control subjects. Using mass spectrometric analysis, we confirmed that HIP11 is present in human islets. This work represents an important step in characterizing the role of CD4 T cell responses to HIPs in human T1D.
Highlights
Type 1 diabetes (T1D) is an autoimmune disease driven by T cells specific for pancreatic b-cell autoantigens
The HIP11-reactive CD4 T cell clone E2 was isolated from the peripheral blood of a patient with type 1 diabetes (T1D) and in a previous study, we determined that the E2 response to HIP11 was restricted to HLA-DQ [6]
Using donor peripheral blood mononuclear cells (PBMCs) partially matched for each haplotype as antigen-presenting cells (APC), we tested the ability of the two haplotypes to stimulate the E2 CD4 T cell clone to HIP11
Summary
Type 1 diabetes (T1D) is an autoimmune disease driven by T cells specific for pancreatic b-cell autoantigens. Identifying b-cell antigens targeted by autoreactive T cells is an important step in understanding the etiopathogenesis of T1D. Post-translational modification of proteins can generate neo-epitopes in the periphery that are not represented in the thymus, providing a mechanism by which autoreactive T cells can evade central tolerance mechanisms and mediate b-cell destruction in the pancreatic islets. Hybrid Insulin Peptide (HIP) formation is a recently discovered modification that may HIP11 Is a T Cell Epitope in T1D play a key role in the generation of primary targets of autoimmunity in T1D [1]. We have identified HIPs in murine and human islets by mass spectrometry [1, 2], and a separate group recently demonstrated that HIPs can be found in the major histocompatibility complex (MHC) class II peptidome of mice [3]
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