Overexpression of Pbx1-d, a novel splice isoform of Pbx1, in CD4+ T cells promotes follicular helper T cell differentiation (BA6P.127)

Abstract

Abstract Pbx1 controls chromatin accessibility to a large number of genes. Pbx1-d is a Pbx1 dominant negative isoform lacking the DNA binding domain, and its expression is more frequent in the CD4+ T cells from lupus patients than in healthy controls. Pbx1-d is associated with the production of autoreactive CD4+ T cells in the Sle1a1 lupus susceptibility locus and lupus susceptibility in the B6.Sle1.Sle2.Sle3 mouse model. We have generated Pbx1-d Tg mice that specifically express Pbx1-d in CD4+ T cells. These Tg mice reproduce the phenotypes of Sle1a1 mice, with increased inflammatory functions of CD4+ T cells and impaired regulatory T (Treg) cell homeostasis. Pbx1-d Tg mice also present an increased number of follicular helper T (TFH) cells, which expand with age in naïve mice, and result in enhanced TH1-biased antibody production in response to T-dependent immunization. Interestingly, the relative distribution of TFH and regulatory T (TFR) cell populations is different in both Pbx1-d Tg and Sle1a1 mice as compared with wild-type mice. Adoptive transfers of OT-II.Pbx1-d Tg CD4+ T cells showed that Pbx1-d overexpression expands TFH cell differentiation in a cell-intrinsic and antigen-specific manner. Our results suggest that Pbx1-d impacts lupus development by regulating effector T cell differentiation by promoting TFH to the expense of Treg cell. In addition, our results identify Pbx1-d as a novel regulator of CD4+ T cell effector function.