The Role of the Wiskott-Aldrich Syndrome Protein in Regulating T Cell Programmed Cell Death Mechanisms and Implications for Autoimmunity in the Wiskott-Aldrich Syndrome.

摘要

The development of autoimmunity in the setting of immunodeficiency has been a paradoxical observation. Many primary immunodeficiency diseases (PIDDs) are associated with autoimmunity. Wiskott-Aldrich Syndrome (WAS), a PIDD caused by defects in the Wiskott-Aldrich Syndrome protein (WASp), has an extremely high percentage of autoimmunity associated among WAS patients (40%). We hypothesized that defects in cell death mechanisms underlie the autoimmunity in WAS. In T cells, since TCR activation involves WASp, and TCR activation is necessary for restimulation induced cell death (RICD), we investigated whether WASp regulates this mechanism of peripheral tolerance. We found that older WASp deficient mice develop autoimmmunity with immune complex nephritis. WASp deficient T cells have a cell-intrinsic defect in RICD and have reduced secretion of secretory granules as well as high molecular weight FasL (HMW FasL). WASp is also required for cytotoxicity of CD4+ T cells, but does not affect the killing of target cell by CD8+ T cells. This was not simply due defects in FasL secretion or CTL granule secretion because Rab27a or FasL deficiency resulted in different defects in target cell killing. The defects we have found in T cell death mechanisms may contribute to the development of autoimmunity in WASp deficient mice and patients with WAS.