STAT1 Affects Lymphocyte Survival and Proliferation Partially Independent of Its Role Downstream of IFN-γ1

Lymphocytes derived from mice deficient in STAT1 showed reduced apoptosis and enhanced proliferation in vitro. To understand the involvement of STAT1 in the observed reduction in apoptosis, we examined the levels of caspase and bcl-2 family genes that are involved in cell survival and/or apoptosis. The levels of caspase 1 and 11, two enzymes involved in both cytokine protein processing and induction of apoptosis, were reduced in STAT1−/− cells compared with wild-type. However, the levels of bcl-2 genes were comparable in both mice. STAT1−/− cells also displayed an enhanced proliferation following TCR stimulation. This hyperproliferation could not be ascribed completely to the loss of IFN-γ-mediated antiproliferation. First, similar phenotypes were also observed in fibroblasts and pre-B cells derived from STAT1−/− mice, which do not produce IFN-γ. Second, comparisons with cells lacking the gene for IFN-γ or with cells treated with neutralizing Abs to IFN-γ only partially mimicked the STAT1−/− phenotype. Interestingly, the kinetics of degradation of p27kip1, a CDK inhibitor, following TCR ligation were faster, and, concomitantly, the up-regulation of CDK2 kinase activity and protein levels were increased in stimulated T cells of STAT1−/− mice relative to those of wild-type mice. Furthermore, STAT1−/− animals were more susceptible to carcinogen-induced thymic tumors, a possible consequence of altered T cell growth and/or survival. These results demonstrate an essential role for STAT1 for lymphocyte survival and proliferation that is only partially dependent on IFN-γ signaling.

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