Paxbp1 restrains cytotoxic and innate cell programs in CD4+ T cells to promote Th2 differentiation

Abstract CD4⁺ T helper cell differentiation is important for efficient host defense and has largely been defined by the activities of a limited number of lineage-specifying transcription factors. However, these factors alone cannot explain the intricate series of events that concurrently induce a specialization program while repressing competing gene programs. In this study, we define a new role for Paxbp1 as an important regulatory factor in T helper cell specification events. We show that Paxbp1 expression is selectively induced in Th2 cells and is required for repression of innate and cytotoxic gene programming potential during Th2 differentiation. Paxbp1-deficiency enhances chromatin accessibility at genomic regions associated with innate lymphocyte programs in both in vitro and in vivo models of Th2 differentiation, indicating that Paxbp1 restrains activities that promote alternative cytotoxic programming potential. Mechanistically, we found Paxbp1 interacts with Bcl11b and Runx1, transcription factors established as negative and positive regulators of innate cytotoxic programming potential, respectively. Our data show that Paxbp1 ensures proper regulation of Bcl11b and Runx1-associated gene programs, and it provides new molecular insights into the complexity of the transcriptional regulatory network involved in CD4⁺ T cell specialization events.