The ubiquitin ligase Cul5 regulates CD4 + T cell fate choice and allergic inflammation.
Binod KumarNatania S FieldDale D KimAsif A DarYanqun ChenAishwarya SureshChristopher F PastoreLi-Yin HungNadia PorterKeisuke SawadaPalak ShahOmar ElbulokEmily K MoserDe'Broski R HerbertPaula M OliverPublished in: Nature communications (2022)
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.
Keyphrases
- cell fate
- dendritic cells
- oxidative stress
- immune response
- regulatory t cells
- chronic obstructive pulmonary disease
- allergic rhinitis
- induced apoptosis
- lung function
- transcription factor
- single cell
- big data
- metabolic syndrome
- adipose tissue
- toll like receptor
- cell cycle arrest
- signaling pathway
- machine learning
- cell therapy
- mesenchymal stem cells
- pi k akt