Fas and p21 suppress autoimmunity by regulating cell cycle progression of effector/memory T cells (167.19)

Abstract

Abstract Fas drives activated T cell apoptosis in vitro, but lymphadenopathy and lupus development in Fas-deficient (lpr) mice cannot be explained only on the basis of the lpr T cell apoptotic defect. Unexplained also remains the in vivo hyperproliferation of T cells in lpr mice, including CD4+, CD8+ and CD4-CD8-TCR+ cells. To date, the effect of lpr T cell-hyperproliferation in both lymphadenopathy and lupus autoimmunity is not known. We investigate this point by generating T cell-specific p21-trangenic -lpr mice. p21, a cell cycle inhibitor and a lupus-like autoimmunity suppressor, regulates the expansion of memory but not of naïve T cells. p21 overexpression in lpr T cells did not affect primary T cell responses, but profoundly diminished lpr T cell proliferation after secondary activation, without affecting the compromised apoptotic cell death of lpr T cells. Importantly, in vivo, p21 overexpression restrains lpr T cell memory expansion, and results in reduced autoantibody production, glomerulonephritis and lymphadenopathy in lpr mice. p21 overexpression did not affect T cell memory in wt mice, pointing to a specialized role for p21 in hyperproliferating T cells. Overall we conclude that lpr T cell hyperproliferation is essential for the increased T cell memory, the autoimmunity and the lymphadenopathy development in lpr mice. Thus, decreasing the hyperproliferation of pathogenic T cells may be of therapeutic value for both Lupus and the Autoimmune Lymphoproliferative Syndrome.