P21 selectively regulates the activation of autoimmune of lpr memory T cells and attenuates autoimmunity (60.5)

Abstract

Abstract Fas drives activated T cell apoptosis in vitro, but lymphadenopathy and lupus in Fas-deficient (lpr) mice cannot be explained only on the basis of the lpr T cell apoptotic defect. Unexplained also remains the hyperproliferation of T cells in lpr mice, including CD4+, CD8+ and CD4-CD8-TCR+ cells. We investigate these questions by generating T cell-specific p21-transgenic and p21-/- BL/6 lpr mice. p21, a cell cycle inhibitor and a lupus-like autoimmunity suppressor, regulates memory T cell but not naïve T cell expansion. p21 overexpression in lpr T cells did not affect primary T cell responses, but profoundly diminished lpr T cell expansion upon repeated activation, without affecting the apoptosis defect of lpr T cells. Importantly, p21 overexpression restrains lpr T cell memory expansion and IFN-gamma and IL-17 production, resulting in reduced autoantibody production, glomerulonephritis and lymphadenopathy in lpr mice. In p21-/- lpr mice, lack of p21 enhanced the activation and accumulation of memory T cells, which produced higher levels of IFN-gamma and IL-17. Lack of p21 led to severe glomerulonephritis and death in BL/6 lpr mice, which normally develop non-lethal mild autoimmunity. Overall, we conclude that independently of their lpr apoptotic defect, T cell hyperactivation and autoimmunity development can be controlled by p21. Thus, analysis of the role of p21 in T cell immunity may be of therapeutic value for both Lupus and the Autoimmune Lymphoproliferative Syndrome.