TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33–driven airway inflammation
Jianxin Xiao, Xing Chen, Weiwei Liu, Wen Qian, Katarzyna Bulek, Lingzi Hong, William Miller-Little, Xiaoxia Li, Caini Liu
Jianxin Xiao, Xing Chen, Weiwei Liu, Wen Qian, Katarzyna Bulek, Lingzi Hong, William Miller-Little, Xiaoxia Li, Caini Liu
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Research Article Immunology Inflammation

TRAF4 is crucial for ST2+ memory Th2 cell expansion in IL-33–driven airway inflammation

Abstract

Tumor necrosis factor receptor–associated factor 4 (TRAF4) is an important regulator of type 2 responses in the airway; however, the underlying cellular and molecular mechanisms remain elusive. Herein, we generated T cell–specific TRAF4-deficient (CD4-cre Traf4fl/fl) mice and investigated the role of TRAF4 in memory Th2 cells expressing IL-33 receptor (ST2, suppression of tumorigenicity 2) (ST2+ mTh2 cells) in IL-33–mediated type 2 airway inflammation. We found that in vitro–polarized TRAF4-deficient (CD4-cre Traf4fl/fl) ST2+ mTh2 cells exhibited decreased IL-33–induced proliferation as compared with TRAF4-sufficient (Traf4fl/fl) cells. Moreover, CD4-cre Traf4fl/fl mice showed less ST2+ mTh2 cell proliferation and eosinophilic infiltration in the lungs than Traf4fl/fl mice in the preclinical models of IL-33–mediated type 2 airway inflammation. Mechanistically, we discovered that TRAF4 was required for the activation of AKT/mTOR and ERK1/2 signaling pathways as well as the expression of transcription factor Myc and nutrient transporters (Slc2a1, Slc7a1, and Slc7a5), signature genes involved in T cell growth and proliferation, in ST2+ mTh2 cells stimulated by IL-33. Taken together, the current study reveals a role of TRAF4 in ST2+ mTh2 cells in IL-33–mediated type 2 pulmonary inflammation, opening up avenues for the development of new therapeutic strategies.

Authors

Jianxin Xiao, Xing Chen, Weiwei Liu, Wen Qian, Katarzyna Bulek, Lingzi Hong, William Miller-Little, Xiaoxia Li, Caini Liu

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Figure 5

TRAF4 is required for IL-33–mediated AKT/mTOR and ERK1/2 pathways as well as signature genes involved in T cell growth and proliferation in ST2+ mTh2 cells.

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TRAF4 is required for IL-33–mediated AKT/mTOR and ERK1/2 pathways as wel...
(A) Cell lysates of in vitro–polarized mouse mTh2 cells treated with or without IL-33 were subjected to the co-immunoprecipitation assay with anti-ST2 antibody, followed by Western blot analysis with the indicated antibodies. WCL, whole cell lysate. (B) In vitro–polarized mouse mTh2 cells (starved in cytokine-free medium for 24 hours) were treated with IL-33 at different time points, and cell lysates were analyzed by Western blot with indicated antibodies. (C) The density of each protein band was quantified by ImageJ (NIH, V. 1.51) and normalized to its total protein or Actin (for TRAF4). Then the fold induction was calculated related to the value of Traf4fl/fl sample at time 0 minutes (which was set to 1) for each protein. (D) Histograms of ST2+ mTh2 cells (treated with IL-33 along with sham or indicated pathway inhibitors) subjected to CFSE cell proliferation assay. (E) Frequency of CFSElo cells. (F) Real-time PCR analysis of the mRNA abundance in mTh2 cells treated with IL-33 for 24 hours. (G and H) Representative histogram blots showing the intracellular expression of MYC and the surface expression of GLUT1 on mTh2 cells treated with sham or IL-33 for 24 hours. Plotted data were shown as means ± SEM. Statistical analysis was performed with 1-way ANOVA (E) or 2-way ANOVA (F). All data are representative of 2 independent experiments.