Evidence for recognition of novel islet T cell antigens by granule-specific T cell lines from new onset type 1 diabetic patients

Type 1 diabetes is a T cell-mediated autoimmune disease where a number of i slet beta-cell target autoantigens have been characterized on the basis of reactivity with autoantibodies. Nevertheless, there remains uncertainty of the nature of another group of autoantigens associated with the secretory g ranule fraction of islet beta-cells that appear to be targeted predominantl y by autoreactive T cells. We have previously characterized CD4(+), HLA-DR- restricted T cell lines from new onset type 1 diabetic patients that are sp ecific for the secretory granule fraction of rat tumour insulinoma, RIN. Th e T cell line from the first patient, HS, proliferates in response to crude microsomal membranes prepared from a recently established, pure human isle t beta-cell line NES2Y. In addition, the HS line also responds to secretory granule fractions prepared from a murine tumour insulinoma grown in RIP-Ta g mice, showing the recognition of species-conserved antigen(s) in beta-cel ls. Using partially matched antigen-presenting cells, the HS T cells and an other line derived from a second patient, MR, were shown to be restricted b y disease-associated DRB1*0101 and DRB1*0404 alleles, respectively. Neither the HS or MR T cell lines proliferate in response to a large panel of cand idate islet cell antigens, including insulin, proinsulin, glutamic acid dec arboxylase, the protein tyrosine phosphatase IA-2/phogrin, imogen-38, ICA69 or hsp60. Our data provide compelling evidence of the presence of a group of antigens associated with the secretory granule fraction of islet beta-ce lls recognized by the T cell lines, whose definition may contribute to our knowledge of disease induction as well as to diagnosis.