Functional characterization of T cells that recognize modified epitopes in patients with type 1 diabetes

Abstract

Abstract Selective recognition of self-proteins that have undergone enzymatic post-translational modification (PTM) by CD4+ T cells is increasingly implicated as a means of potentiating the loss of tolerance in autoimmune diseases such as type 1 diabetes (T1D). In particular, enzymatic deamidation and citrullination of beta cell derived peptides at HLA anchor residues enhances their presentation by high risk alleles (DR4 and DQ8). Modification of residues outside of binding pockets alter T cell recognition, resulting in enhanced proliferation and increased cytokine production. Our work demonstrates that CD4+ T cells specific for PTM epitopes are present in the peripheral blood of patients with T1D at significantly higher ex vivo frequencies than in HLA matched controls. Upon re-activation, PTM specific T cells from T1D patients produce elevated levels of effector cytokines, most notably interferon gamma. Among T1D patients, we observed heterogeneous frequencies of PTM specific T cells with a range of functional profiles. This led us to hypothesize that activation of a PTM specific T cell response is of particular significance in a subset of T1D patients. To test this hypothesis we compared the ex vivo frequency and functional profiles of PTM specific T cells in a cross sectional cohort of patients selected to include diverse levels of residual c-peptide. Our findings implicate a mechanistic role for PTMs in exacerbating autoreactive T cell responses in T1D.