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

• Published in: JCI insight Vol. 8; no. 18
• Main Authors: Xiao, Jianxin, Chen, Xing, Liu, Weiwei, Qian, Wen, Bulek, Katarzyna, Hong, Lingzi, Miller-Little, William, Li, Xiaoxia, Liu, Caini
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 22.09.2023; American Society for Clinical investigation
• Subjects: Animals; Cell Proliferation; Immunology; Inflammation; Inflammation - metabolism; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-33 - genetics; Interleukin-33 - metabolism; Lung - metabolism; Mice; Th2 Cells - metabolism; TNF Receptor-Associated Factor 4 - metabolism; Allergy; Inflammation; Immunology; Cytokines; Cellular immune response
• ISSN: 2379-3708; 2379-3708
• DOI: 10.1172/jci.insight.169736

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.