Normal thymic selection, normal viability and decreased lymphoproliferation in T cell receptor‐transgenic CTLA‐4‐deficient mice

AbstractCTLA‐4 is a T cell surface receptor essential for the negative regulation of T cell activation. In the CTLA‐4‐deficient mouse, a dramatic accumulation of activated peripheral T cells effects extensive damage to host tissues, resulting in mortality within 5 weeks of age. To determine whether the accumulation of activated T cells in CTLA‐4−/− mice is due to a defect in thymic selection, we examined negative selection in CTLA‐4−/− mice using two transgenic T cell receptor (TCR) models of thymic selection. Neither the H‐Y‐specific TCR nor the lymphocytic choriomeningitis virus (LCMV)‐specific TCR transgenic models revealed a defect in positive or negative selection in CTLA‐4−/− mice in vivo or in vitro. In fact, the negatively selecting phenotype of male H‐YTCR‐transgenic mice greatly mitigated the accumulation of activated peripheral T cells. Further, peripheral CTLA‐4−/− T cells expressing a single LMCV‐specific transgenic TCR did not have an activated phenotype, indicating that CTLA‐4−/− T cells require specific antigen for proliferation. These results demonstrate that specific antigen is required for the lymphoproliferation observed in CTLA‐4−/− mice, and that CTLA‐4 deficiency does not lead to a gross defect in negative selection.