The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation.

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. Cytokine signaling influences the differentiation of CD4⁺ T cells into varying functional subsets. Here the authors show that an E3 ubiquitin ligase Cul5 alters T_H2 and T_H9 development and absence of Cul5 in T cells results in higher levels of allergy-associated IL-4 and IL-9 secreting T cells. [ABSTRACT FROM AUTHOR]