RAS P21 Protein Activator 3 (RASA3) specifically promotes pathogenic T helper 17 cell generation by repressing T helper 2-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
• 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-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-biased program that dominantly trans -suppressed pTh17 cell generation via interleukin 4 production. The Th2-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 programs. These findings indicate that a distinct molecular program directs pTh17 generation and reveals targets for treating pTh17-related pathology and diseases.