3 years ago

IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells

IL-6 receptor blockade corrects defects of XIAP-deficient regulatory T cells
Ming-Zong Lai, Ya-Jen Chang, Tzu-Sheng Hsu, Wan-Chen Hsieh
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.

Publisher URL: https://www.nature.com/articles/s41467-018-02862-4

DOI: 10.1038/s41467-018-02862-4

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