Opposing roles of SWI/SNF chromatin remodeling complex BAF and PBAF in Effector Differentiation during Chronic Viral Infection

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Presentation Time: 03:15 PM - 04:30 PM
Poster Board Number: B726
Abstract ID: 5810

Presenting Author:
Arjun Kharel , Graduate Student at Northwestern Univ. Feinberg Sch. of Med.

Abstract:

During chronic viral infection, CD4⁺ T cells help in the form of IL-21 is critical for the development of highly cytolytic effector CD8⁺ T cells. However, the exact signaling pathways from IL-21 that regulate CD8⁺ T cell function remain unclear. The current dogma states that IL-21 predominantly signals through STAT3, to generate effector CD8⁺ T cells during chronic viral infection.

Here, we reveal a novel mechanism of IL-21 signaling via STAT4 for effector CD8⁺ T cell development following chronic LCMV infection. Furthermore, STAT4-mediated effector differentiation is epigenetically regulated by BAF, a SWI/SNF chromatin remodeling complex. In the absence of either STAT4 or BAF, virus specific CD8⁺ T cells fail to differentiate into highly cytolytic effector CD8⁺ T cells capable of controlling viral infection.

The effector differentiation phenotype is balanced by PBAF, another component of the SWI/SNF complex, which promotes CD8⁺ T cell exhaustion during chronic LCMV infection. Conditional knockout of PBAF from CD8⁺ T cells impairs the development of T cell exhaustion, resulting in immunopathology and mortality of chronic LCMV-infected mice. Interestingly, this phenotype is dependent on the STAT4 and BAF-mediated transcriptional and chromatin changes. Overall, our findings underscore the delicate balance between effector and exhaustion pathways, governed by BAF and PBAF complex, to dictate the outcomes of immunopathology during chronic viral infections.