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 1

TRAF4 deficiency impairs IL-33–mediated proliferation of in vitro–polarized ST2+ mTh2 cells.

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TRAF4 deficiency impairs IL-33–mediated proliferation of in vitro–polari...
(A) Wild-type, floxed, and conditional knockout alleles of mouse Traf4 are depicted schematically. (B) Naive CD4+ T cells, isolated from T cell–specific TRAF4-deficient (CD4-cre Traf4fl/fl) and TRAF4-sufficient (Traf4fl/fl) mice, were differentiated under Th2 conditions for 5 days to generate effector Th2 (effTh2) cells; effTh2 cells were then cultured (with IL-2 and IL-7 only) for 10 days to obtain mTh2 cells (mTh2). mTh2 cells were then treated with sham (UT) or IL-33 for 3 days before indicated analysis (C–K). (C) Representative flow cytometry plots of effTh2 and sham- and IL-33–treated mTh2 cells. (D) Absolute numbers of ST2+ mTh2 cells. (E) Histograms of Ki-67+ST2+ mTh2 cells. Filled histograms represent the cell population stained by the Ki-67 antibody, and the unfilled histograms represent the cell population stained by the isotype control antibody. (F) Absolute numbers of Ki-67+ST2+ mTh2 cells. (G) Histograms of IL-33–treated ST2+ mTh2 cells subjected to CFSE cell proliferation assay. (H) Absolute numbers of CFSElo cells. (I) Histograms of apoptotic mTh2 cells (FITC+). (J) Absolute numbers of apoptotic mTh2 cells. (K) IL-5 and IL-13 protein concentrations in cell medium were quantified by ELISA. Plotted data were shown as means ± SEM. Statistical analysis was performed with 1-way ANOVA (H) or 2-way ANOVA (D, F, G, and K). All data are representative of 3 independent experiments.