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 challenges. From this analysis, we found Paxbp1, a poorly described nuclear factor, was highly expressed in Th2 cells and its expression correlated well with Gata3. To date, Paxbp1 has been shown to play a vital role in muscle stem cells, but our data suggests an unrecognized role in T helper and T cell development. Although Paxbp1 is ubiquitously expressed, we found that it had the potential to be dynamically regulated in lymphocytes. 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 leads to a decrease in naive T cells. Moreover, loss of Paxbp1 results in an aberrant expression of a Type I program. This increased expression was seen in T cells exposed to a type 2 environment in both a reductionist and natural type 2 polarization. Specifically, Paxbp1 deficiency results in the expression of what appears to be a terminal cytotoxic program. Previously, Paxbp1 has been shown to play an important role in muscle stem cells for exiting a quiescent state, particularly in proliferation and metabolism. Preliminary data indicates that this may be the case for lymphocytes as well. Altogether, our data suggests that Paxbp1 may be a previously unrecognized player in T helper specification and development that constrains inappropriate expression and accessibility of programs employed by alternative lymphocyte lineages.