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

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)