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.

抗原接触可指导CD4阳性T细胞（CD4+ T cells）分化为辅助性T细胞（T-helper cells）或调节性T细胞（T-regulatory cells）。该过程将免疫应答聚焦于入侵的病原体，并限制组织损伤。调控辅助性T细胞与调节性T细胞命运分化的分子机制仍不甚明确。
本研究发现，E3泛素连接酶（E3 ubiquitin ligase）Cul5可通过调控白细胞介素4受体（IL-4 receptor）信号通路，决定CD4阳性T细胞的命运选择。
T细胞中Cul5缺失的小鼠，在过敏原暴露后可出现增强的2型辅助性T细胞（Th2）与9型辅助性T细胞（Th9）炎症反应，以及特应性哮喘（atopic asthma）的病理生理学特征。
T细胞活化后，Cul5可与CIS及磷酸化JAK1（pJak1）形成复合物。Cul5功能缺失会导致pJak1的泛素化水平降低、稳定性增强，STAT6活性升高，并降低IL-4受体信号通路的激活阈值。
与此一致，在低浓度IL-4的培养条件下，Cul5缺陷的T细胞会偏向于从调节性T细胞向Th9细胞分化。上述数据表明，Cul5可促进免疫耐受型T细胞的命运选择，并降低机体对过敏性哮喘的易感性。
实验设计：对野生型（WT）与CD4-Cre介导的Cul5基因敲除（Cul5-/- CD4Cre）小鼠的脾脏及淋巴结中分离的经Th9极化的CD4阳性T细胞进行RNA测序（RNA-seq）。