GSE184321
Cul5 regulates CD4+ T cell fate choice and allergic inflammation [RNA-seq]
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 -helper versus -regulatory 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 developed enhanced Th2 and Th9 inflammation and pathophysiological features of atopic asthma upon allergen exposure. Following T cell activation, Cul5 formed a complex with CIS and pJak1. Loss of Cul5 function resulted in reduced ubiquitylation and increased stability of pJak1, elevated STAT6 activity, and a reduced threshold for IL-4 receptor signaling. In accordance with this, Cul5-deficient T cells deviated from Treg to Th9 differentiation in low IL-4 conditions. These data support that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma. Overall design: RNA-seq of Th9 polarized CD4 T cells from spleens/lymph nodes of WT vs. Cul5-/- CD4Cre mice.