Work

The PBAF chromatin remodeling complex maintains progenitor quiescence and drives exhaustion to avert effector differentiation and prevent immunopathology during persistent infection 4587

Year: 2025

Type: article

Abstract: Description During chronic viral infection and cancer, CD8 T cells undergo a physiological adaptation known as T cell exhaustion. While most T cells in the exhausted pool are terminally differentiated, the Progenitor subset can self-renew, promote Effector differentiation, and respond to immune checkpoint blockade. Despite persistent antigen exposure, how Progenitors remain quiescent and what maintains the Effector-Exhausted pool balance is not well known. Our study highlights key roles of the SWI/SNF chromatin remodeling complexes, BAF and PBAF, in regulating CD8 T cell fates during persistent infection. Conditional deletion of PBAF in CD8 T cells results in a loss of progenitor subsets during the later phase of chronic LCMV infection. Molecular studies reveal that PBAF maintains progenitor quiescence by promoting accessibility and maintaining higher-order chromatin structure at stemness-associated genes such as Tcf7. In the effector branch, we reveal a novel signaling cascade where IL-21 activates STAT4 to drive effector differentiation. This STAT4 mediated effector differentiation is epigenetically regulated by the BAF complex. Deletion of either STAT4 or BAF in CD8 T cells results in a loss of Effector differentiation during chronic LCMV infection. In the absence of PBAF, the IL-21/STAT4/BAF signaling drives excessive effector differentiation, causing severe immunopathology and mortality—highlighting the key role of PBAF-mediated quiescence and exhaustion to prevent immunopathology. Funding Sources This work is supported by NIH grants AI148403 (Weiguo Cui). Topic Categories Lymphocyte Differentiation and Peripheral Maintenance (LYM)

Source: The Journal of Immunology

DOI: 10.1093/jimmun/vkaf283.2254