PAXBP1 SERVES AS A NOVEL REGULATOR OF T HELPER SPECIFICATION BY RESTRAINING THE TYPE 1 PROGRAM

Abstract

Abstract To properly extinguish a diverse number of pathogens naïve T cells speciate into several T helper subsets in a highly regulated manner. In order to identify novel regulators of T helper specification we explored single cell RNA-seq datasets of T cells exposed to several different 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. 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. Analysis from scRNA-seq reveal that Paxbp1 deficiency leads to a decrease in mature naïve T cells in both the thymus and periphery. Moreover, loss of Paxbp1 results in an aberrant expression of a Type I program, despite being exposed to a Type 2 environment in a reductionist approach; specifically, Paxbp1 deficiency results in the expression of what appears to be a terminal cytotoxic program. During in vivo challenges, T cells from Paxbp1 deficient animals recapitulated these results showing an increase in expression of the Type 1 program. Current work is aimed at determining the function of Paxbp1 by identifying binding partners through mass spectrometry. Additionally, we will use scATAC-seq to define transcription factors with differential activity in Paxbp1 deficient T cells. 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.