Loss of tolerance due to post-translational modification of beta cell peptides (BA11P.124)

Abstract

Abstract Post-translational modification (PTM) of self-proteins generates neo-antigens that are clinically relevant to autoimmune disease and are increasingly implicated in T1D. Here we demonstrate that enzymatic transglutamination and citrullination of beta cell antigens enhances presentation by the high risk HLA class II alleles DR4 and DQ8. We show CD4+ T cells specific for these epitopes are present at elevated frequencies ex vivo in the peripheral blood of patients with long standing T1D and are of Th1 phenotype. Such neo-antigens can induce distinct T cell specificities, while others cross-react with wild type-specific T cells. In each case, autoreactive T cells preferentially recognize modified epitopes resulting in enhanced proliferation and cytokine production. Mechanistically, modification at key binding pockets enhanced peptide binding to HLA class II, creating a stable pMHC that could bind autoreactive CD4+ T cells. Alternatively, modification of residues outside of binding pockets altered TCR interaction to permit T cell recognition. In one instance, dual modification of HLA and TCR contact points was required to induce a T cell response. Interrogation of autoantibody positive, healthy “non-progressors” revealed an intermediate T cell frequency, representing a break in tolerance without progression to overt diabetes. These findings implicate an important role for PTMs in broadening the antigenic repertoire and exacerbating the evolving autoimmune response in T1D.