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

Binod Kumar, Natania S. Field, Dale D. Kim, Asif A. Dar, Yanqun Chen, Aishwarya Suresh, Christopher F. Pastore, Li-Yin Hung, Nadia Porter, Keisuke Sawada, Palak Shah, Omar Elbulok, Emily K. Moser, Herbert De’Broski R. and Paula M. Oliver ()
Additional contact information
Binod Kumar: The Children’s Hospital of Philadelphia
Natania S. Field: The Children’s Hospital of Philadelphia
Dale D. Kim: The Children’s Hospital of Philadelphia
Asif A. Dar: The Children’s Hospital of Philadelphia
Yanqun Chen: The Children’s Hospital of Philadelphia
Aishwarya Suresh: The Children’s Hospital of Philadelphia
Christopher F. Pastore: University of Pennsylvania School of Veterinary Medicine
Li-Yin Hung: University of Pennsylvania School of Veterinary Medicine
Nadia Porter: The Children’s Hospital of Philadelphia
Keisuke Sawada: The Children’s Hospital of Philadelphia
Palak Shah: The Children’s Hospital of Philadelphia
Omar Elbulok: The Children’s Hospital of Philadelphia
Emily K. Moser: The Children’s Hospital of Philadelphia
Herbert De’Broski R.: University of Pennsylvania School of Veterinary Medicine
Paula M. Oliver: The Children’s Hospital of Philadelphia

Nature Communications, 2022, vol. 13, issue 1, 1-14

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.

Date: 2022
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DOI: 10.1038/s41467-022-30437-x

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