Early Th1 response in unprimed nonobese diabetic mice to the tyrosine phosphatase-like insulinoma-associated protein 2, an autoantigen in type 1 diabetes

The insulinoma-associated protein 2 (IA-2) is a phosphatase-like autoantige n inducing T and B cell responses associated with human insulin-dependent d iabetes mellitus (IDDM), We now report that T cell responses to IA-2 can al so be detected in the nonobese diabetic (NOD) mouse, a model of human IDDM. Cytokine secretion in response to purified mouse rIA-2, characterized by h igh IFN-gamma and relatively low IL-10 and IL-6 secretion, was elicited in spleen cells from unprimed NOD mice. Conversely, no response to IA-2 was in duced in spleen cells from BALB/c, C57BL/6, or Biozzi AB/H mice that expres s, like NOD, the I-A(g7) class II molecule, but are not susceptible to spon taneous IDDM. The IA-2-induced IFN-gamma response in NOD spleen cells could already be detected at 3 wk and peaked at 8 wk of age, whereas the IL-10 s ecretion was maximal at 4 wk of age and then waned. IA-2-dependent IFN-gamm a secretion was induced in CD4(+) cells from spleen as well as pancreatic a nd mesenteric lymph nodes, It required Ag presentation by I-A(g7) molecules and engagement of the CD4 coreceptor. Interestingly, cytokines were produc ed in the absence of cell proliferation and IL-2 secretion. The biological relevance of the response to IA-2 is indicated by the enhanced IDDM followi ng a single injection of the recombinant protein emulsified in IFA into 18- day-old NOD mice. In addition, IFN-gamma production in response to IA-2 and IDDM acceleration could be induced by IL-12 administration to 12-day-old N OD mice. These results identify IA-2 as an early T cell-inducing autoantige n in the NOD mouse and indicate a role for the IA-2-induced Th1 cell respon se in IDDM pathogenesis.