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

Nat Commun. 2018 Jan 31;9(1):463. doi: 10.1038/s41467-018-02862-4.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Forkhead Transcription Factors / metabolism
  • Genetic Diseases, X-Linked / immunology*
  • Humans
  • Interferon-gamma / metabolism
  • Lymphoproliferative Disorders / immunology*
  • Mice
  • Mice, Knockout
  • Protein Stability
  • Receptors, Interleukin-6 / antagonists & inhibitors*
  • Suppressor of Cytokine Signaling 1 Protein / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • T-Lymphocytes, Regulatory / metabolism
  • X-Linked Inhibitor of Apoptosis Protein / genetics

Substances

  • FOXP3 protein, human
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Receptors, Interleukin-6
  • Suppressor of Cytokine Signaling 1 Protein
  • X-Linked Inhibitor of Apoptosis Protein
  • Interferon-gamma

Supplementary concepts

  • Lymphoproliferative Syndrome, X-Linked, 2