T cell reactivity to DR*0401-and DQ*0302-binding peptides of the putative autoantigen IA-2 in type 1 diabetes

Type 1 diabetes is thought to be an autoimmune disease mediated by T lympho cytes recognizing critical islet cell antigens. Recently, the tyrosine phos phatase like protein IA-2 was suggested as a putative autoantigen in type 1 diabetes since autoantibodies are detected in sera of diabetic patients an d prediabetic subjects. Similarly, T cell responses of peripheral blood lym phocytes of type 1 diabetic patients to this protein have been described. O nly very few data is available about immunodominant epitopes of IA-2 recogn ized by T cells. We have studied T cell responses in type 1 diabetic patien ts and age and partly HLA matched controls to IA-2 peptides designed to bin d HLA risk alleles of IDDM as DR* 0401 and DQ*0302. Both diabetic patients and controls responded to IA-2ic and some of the peptides. Three peptides o f the C-terminal region of IA-2 were recognised by T cells of a fraction of diabetic patients but at least two of these peptides triggered also T cell responses in DR*0401/DQ*0302-matched controls Most peptides bound to diffe rent HLA alleles ("promiscous binders"). The identification of autoantigeni c epitopes may offer clues to related sequences e.g. of viral origin what r elates to models of diabetes pathogenesis ("molecular mimicry"). Secondly, the design of antigen- or even epitope-specific immune intervention strateg ies aiming at tolerization of disease specific T cells in type 1 diabetes m ay profit from the knowledge of immunodominant T cell epitopes of a putativ e autoantigen.