The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation
Binod Kumar, Natania S. Field, Dale Kim, Asif A. Dar, Yan Chen, Aishwarya Suresh, Christopher Pastore, Li‐Yin Hung, Nadia Porter, Keisuke Sawada, Palak Shah, Omar A. Elbulok, Emily K. Moser, De’Broski R. Herbert, Paula M. Oliver
Abstract
Abstract Antigen encounter directs CD4 + T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4 + T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4 + T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.