PANCREATIC EXPRESSION OF B7 COSTIMULATORY MOLECULES IN THE NONOBESE DIABETIC MOUSE

Expression of the co-stimulatory molecule B7-1 (CD80) on pancreatic be ta cells can overcome peripheral T cell tolerance in transgenic models of autoimmune disease. This study aimed to determine if aberrant B7-1 or B7-2 (CD86) expression on pancreatic beta cells is involved in the pathogenesis of autoimmune diabetes in non-obese diabetic (NOD) mice. Immunohistochemical analysis of NOD pancreas sections revealed no evi dence of B7-1 or B7-2 expression on pancreatic beta cells at any stage prior to the onset of either spontaneously arising or cyclophosphamid e-accelerated diabetes. Likewise, the NOD-derived NIT-1 beta cell line did not express surface B7 or B7-1 mRNA either constitutively or foll owing exposure to IFN-gamma and TNF-alpha, two cytokines known to be p resent in the insulitis lesion of NOD mice, or cAMP which can induce B 7-1 expression on B cells. Both B7-1 and B7-2 were, however, highly ex pressed on the majority of islet-infiltrating inflammatory cells in NO D mice between days 7 and 12 after the administration of cyclophospham ide which results in accelerated beta cell destruction. Likewise B7-1 and B7-2 were extensively expressed on islet-infiltrating cells presen t at the time of diabetes onset in NOD SCID mice with adoptively trans ferred diabetes. By immunohistochemisty and flow cytometry, it was det ermined that the phenotype of B7(+) cells in the pancreas of NOD mice 9 days after cyclophosphamide included a mixture of macrophages and bo th CD4(+) and CD8(+) T cells. B7-2 was also expressed on islet-infiltr ating cells in the spontaneously occurring diabetes of female NOD mice , but the levels of B7-1 expression were low in comparison with the ac celerated models of diabetes. RIP-IL-2 transgenic mice, which have ext ensive islet infiltration but no autoimmune beta cell destruction, als o had virtually no B7-1 expression and a minority of B7-2-expressing i nflammatory cells. Thus, the activation of beta cell-specific T cells in NOD mice does not appear to be a result of aberrant expression of B 7 on the beta cells. Expression of B7-1 and B7-2 on islet-infiltrating cells is, however, associated with autoimmune beta cell destruction, suggesting a role for the B7-CD28 interaction in this process.