THYMUS DYSFUNCTION AND CHRONIC INFLAMMATORY DISEASE IN GP39 TRANSGENIC MICE

Expression of gp39 on activated T cells provides a co-stimulatory sign al in peripheral lymphoid tissue that regulates humoral and cell-media ted immunity. The function of gp39 and its receptor CD40 in thymus rem ains uncertain, Here we report that overexpression of gp39 in transgen ic mouse thymus caused a dose-dependent decline in thymocyte numbers ( >500 fold), loss of cortical epithelium and expansion of CD40(+) medul lary cells. Transplantation of transgenic bone marrow into normal mice indicated that gp39 significantly diminished thymocyte viability in t he context of a 'normal' thymic environment. The peripheral tissues of transgenic mice also accumulated abnormalities in a transgene dose-de pendent manner that involved inflammation and lymphoid tissue hypertro phy. Animals with the highest transgene copy numbers acquired a lethal inflammatory bowel disease marked by the infiltration of gp39(+) T ce lls and CD40(+) cells into diseased tissues, Examination of cells over expressing gp39 suggested that these defects were caused, in part, by the saturation of a mechanism that sequesters gp39 inside non-activate d cells and thus protects the immune system from inappropriate gp39-CD 40 interaction, These results establish a regulatory role for gp39 in thymus function and a causal relationship in mediating chronic inflamm atory disease.