E3 Ubiquitin Ligase Cbl-b Suppresses Proallergic T Cell Development and Allergic Airway Inflammation

G. Qiao, H. Ying, Y. Zhao, Y. Liang, H. Guo, H. Shen, Z. Li, J. Solway, E. Tao, Y. Chiang, S. Lipkowitz, J.M. Penninger, Wallace Langdon, J. Zhang

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49 Citations (Scopus)

Abstract

E3 ubiquitin ligase Cbl-b has emerged as a gatekeeper that controls the activation threshold of the Tcell antigen receptor and maintains the balance between tolerance and autoimmunity. Here, we report that the loss of Cbl-b facilitates T helper 2 (Th2) and Th9 cell differentiation invitro. In a mouse model of asthma, the absence of Cbl-b results in severe airway inflammation and stronger Th2 and Th9 responses. Mechanistically, Cbl-b selectively associates with Stat6 upon IL-4 ligation and targets Stat6 for ubiquitination and degradation. These processes are heightened in the presence of Tcell receptor (TCR)/CD28 costimulation. Furthermore, we identify K108 and K398 as Stat6 ubiquitination sites. Intriguingly, introducing Stat6 deficiency into Cblb-/- mice abrogates hyper-Th2 responses but only partially attenuates Th9 responses. Therefore, our data reveal a function for Cbl-b in the regulation of Th2 and Th9 cell differentiation. © 2014 The Authors.
Original languageEnglish
Pages (from-to)709-723
JournalCell Reports
Volume6
Issue number4
DOIs
Publication statusPublished - 2014

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