Defining the role of Paxbp1 in T cell development and T helper specification

National Institute Of Arthritis And Musculoskeletal And Skin Diseases

Investigators

Abstract

Once activated, T cells have the capacity to differentiate into various T helper subsets. For T cells to properly extinguish a diversity of pathogens, T helper specification is highly regulated. To identify novel regulators of T helper specification we explored single cell datasets of T cells exposed to various primary immune challenges. From this analysis, we found Paxbp1, a poorly described nuclear factor, was highly expressed in Th2 cells with its expression correlating well with Gata3. Initially characterized in muscle stem cells, Paxbp1 has been shown to play a vital role for their differentiation and survival. More recently, Paxbp1 has been shown to play a role in the survival of T cells in both the thymus and peripheral lymphoid organs. Our data extends our understanding of the role of Paxbp1 in T cells by developing a molecular characterization of its role in Th2 cell differentiation. Although Paxbp1 is ubiquitously expressed, we found that it possessed dynamic expression in different lymphocyte subsets. To understand the role Paxbp1 plays in T helper differentiation, we generated a mouse model where Paxbp1 was deleted in T cells using a CD4cre model. Paxbp1 deficiency results in an aberrant expression of a cytotoxic program in CD4+ T cells during Type 2 polarization. This skewing to express a cytotoxic program despite differentiating in a type 2 environment was observed in both a reductionist in vitro culture condition and natural type 2 polarization (OVA-asthma model, Nippo). Using both bulk and single cell next generation sequencing technologies we have observed that CD4+ T cells deficient in Paxbp1 have increased expression and chromatin accessibility of cytotoxic genes. Interestingly, our data suggests that in part this could be mechanistically due to a potential relationship between Paxbp1 and lineage defining transcription factors. Collectively, our data suggest that Paxbp1 plays an important role in T cell differentiation and an important molecule to study.