RAS P21 Protein Activator 3 (RASA3) Specifically Promotes Pathogenic T Helper 17 Cell Generation by Repressing T-Helper-2-Cell-Biased Programs

• Published in: Immunity (Cambridge, Mass.) Mass.), 2018-11, Vol.49 (5), p.886-898.e5
• Main Authors: Wu, Bing, Zhang, Song, Guo, Zengli, Wang, Gang, Zhang, Ge, Xie, Ling, Lou, Jitong, Chen, Xian, Wu, Di, Bergmeier, Wolfgang, Zheng, Junnian, Wan, Yisong Y.
• Format: Article
• Language: English
• Subjects: Animals; Autoimmunity; Biomarkers; Cbl protein; Cbl-b; Cbl-b protein; Cell Differentiation - genetics; Cyclin-dependent kinase inhibitor p21; Cytokines; EAE disease; Encephalomyelitis, Autoimmune, Experimental - etiology; Encephalomyelitis, Autoimmune, Experimental - metabolism; Encephalomyelitis, Autoimmune, Experimental - pathology; Experimental allergic encephalomyelitis; Experiments; Gene Expression; GTP-binding protein; GTPase-Activating Proteins - genetics; GTPase-Activating Proteins - metabolism; Helper cells; Homeostasis; IL-4; Immunophenotyping; Interferon regulatory factor 4; Interferon Regulatory Factors - genetics; Interferon Regulatory Factors - metabolism; Interleukin 4; IRF4; Lymphocytes; Lymphocytes T; Mice; pathogenic Th17 cell; pathogenic Th17-Th2 reciprocal programs; Pathology; Proteasomes; Proteins; Proteolysis; Ras protein; RASA3; RNA, Messenger; Th17 Cells - cytology; Th17 Cells - immunology; Th17 Cells - metabolism; Th2 Cells - cytology; Th2 Cells - immunology; Th2 Cells - metabolism; Ubiquitin; Ubiquitin-protein ligase
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2018.09.004

Pathogenic Th17 (pTh17) cells drive inflammation and immune-pathology, but whether pTh17 cells are a Th17 cell subset whose generation is under specific molecular control remains unaddressed. We found that Ras p21 protein activator 3 (RASA3) was highly expressed by pTh17 cells relative to non-pTh17 cells and was required specifically for pTh17 generation in vitro and in vivo. Mice conditionally deficient for Rasa3 in T cells showed less pathology during experimental autoimmune encephalomyelitis. Rasa3-deficient T cells acquired a Th2 cell-biased program that dominantly trans-suppressed pTh17 cell generation via interleukin 4 production. The Th2 cell bias of Rasa3-deficient T cells was due to aberrantly elevated transcription factor IRF4 expression. RASA3 promoted proteasome-mediated IRF4 protein degradation by facilitating interaction of IRF4 with E3-ubiquitin ligase Cbl-b. Therefore, a RASA3-IRF4-Cbl-b pathway specifically directs pTh17 cell generation by balancing reciprocal Th17-Th2 cell programs. These findings indicate that a distinct molecular program directs pTh17 cell generation and reveals targets for treating pTh17 cell-related pathology and diseases. [Display omitted] •Pathogenic Th17 cell generation requires RASA3•RASA3 is vital for the pathogenicity of T cells in EAE•RASA3 restricts IRF4-dependent Th2 cell programs to favor pTh17 cell programs•RASA3 interacts with Cbl-b to promote IRF4 protein degradation Pathogenic Th17 cells promote immune pathology, but how their generation is controlled remains largely unknown. Wu et al. reveal that RASA3 is essential for pathogenic Th17 cell generation but dispensable for non-pathogenic Th17 cell generation. RASA3 functions by repressing Th2 cell programs in pathogenic Th17 cells by fine-tuning IRF4 protein expression.