X-linked lymphoproliferative syndrome type-2 (XLP-2) is a primary immunodeficiency disease attributed to XIAP mutation and is triggered by infection. Here, we show that mouse Xiap regulatory T (Treg) cells and human XIAP-deficient Treg cells are defective in suppressive function. The Xiap Treg cell defect is linked partly to decreased SOCS1 expression. XIAP binds SOCS1 and promotes SOCS1 stabilization. Foxp3 stability is reduced in Xiap Treg cells. In addition, Xiap Treg cells are prone to IFN-γ secretion. Transfer of wild-type Treg cells partly rescues infection-induced inflammation in Xiap mice. Notably, inflammation-induced reprogramming of Xiap Treg cells can be prevented by blockade of the IL-6 receptor (IL-6R), and a combination of anti-IL-6R and Xiap Treg cells confers survival to inflammatory infection in Xiap mice. Our results suggest that XLP-2 can be corrected by combination treatment with autologous iTreg (induced Treg) cells and anti-IL-6R antibody, bypassing the necessity to transduce Treg cells with XIAP.
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| http://dx.doi.org/10.1038/s41467-018-02862-4 | DOI Listing |
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