Defects of Regulatory T Cell function In The Wiskott-Aldrich Syndrome.

Abstract Natural Tregs from both WAS patients and WASp-deficient (WKO) mice were previously reported as unable to suppress the proliferation of conventional T-cells in vitro. Because WAS T-cells have a known defect of IL-2 production and this cytokine is important for the generation of Treg cells induced from naïve T-cells, we assessed the efficiency with which WKO naïve T-cells can differentiate in Tregs and observed a significant defect compared to WT. Such defect was not corrected by increasing concentration of anti-CD3 and TGF-β. Preliminary experiments indicated a role for endogenous IL-2 production in the generation of iTregs and pointed again to the IL-2 pathway as a major determinant of the Treg cells defects in WAS. Furthermore, we previously observed that the impaired suppression of T-cell proliferation could be partially rescued by pre-activation of nTregs. Because activated nTregs are known to be able to induce B-cell apoptosis, we set out to evaluate the function of WKO nTregs on B-cells. We found that pre-activated WKO Treg cells fail to effectively suppress B-cell proliferation. The reduced granzyme-B secretion by WKO nTregs compared to WT, suggest that the defective suppressive activity on B-cells may be due to a degranulation defect of WKO cells. In summary, our data suggest that both natural and induced arms of T regulatory cells are defective in WAS and that defective peripheral Treg induction may be involved in the pathogenesis of autoimmunity in this disease.