The E3 Ubiquitin ligase Cul4b is required for CD8+ T cell-mediated antiviral immunity

Autor: Asif Amin Dar, Scott Gordon, Kathleen Klinzing, Kim Dale, Nadia Porter, Ipsita Guha, Edward M Behrens, Paula M Oliver
Rok vydání: 2022
Předmět:
Zdroj: The Journal of Immunology. 208:57.06-57.06
ISSN: 1550-6606
0022-1767
Popis: CD8+ T cells play crucial roles in cellular immune mechanisms that clear invading viruses and prevent reinfection. Virus specific CD8+ T cells expand approximately 10,000 fold, undergoing up to 20 cell divisions in the first week of infection. While this rapid expansion is needed to reduce viral loads, replication can lead to DNA damage and telomere shortening, resulting in growth arrest. T cells must be equipped with mechanisms that promptly promote DNA repair to protect cells from premature senescence and death. We recently determined that the E3 Ubiquitin ligase Cullin-4b (Cul4b) regulates genome integrity in CD4+ T cells by helping to resolve DNA damage. In keeping with this, aberrant expression of Cul4b and its ortholog Cul4a has been reported in many cancers. However, whether Cul4b is important in controlling CD8+ T cell numbers or viral clearance is not known. To address this, we infected control and Cul4bcKO mice with LCMV. Following infection, virus-specific CD8+ T cells lacking Cul4b failed to expand or acquire effector functions. As a consequence, Cul4bcKO mice were unable to clear LCMV. Furthermore, Cul4b-deficient CD8+ T cells were unable to differentiate into memory T cells. Using IP and tandem mass spectrometry, we found Cul4b associated with the chromatin remodeling BAF complex (SWI/SNF). Specifically, our data supports that Brg1, a component of SWI/SNF complex, is a client of the Cul4b ubiquitin ligase. Loss of Cul4b increased Brg1 binding to chromatin following CD8+ T cell activation, impacting gene expression and/or cell cycle arrest. Together, these data support that Cul4b limits the amount of Brg1 associated with chromatin, and allows the expansion and differentiation of CD8+ T cells thus promoting antiviral immunity.
Databáze: OpenAIRE
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