Overexpression of Pbx1-d, a novel splice isoform of Pbx1, changes the portion of follicular CD4 T cell populations and impairs regulatory T cell homeostasis (BA14P.201)

Abstract

Abstract We have previously shown that the differential expression of a novel splice isoform, Pbx1-d, of the Pbx1 gene was 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. Pbx1 regulates the transcription of a large number of genes by controlling chromatin accessibility. Pbx1-d is the only known Pbx1 isoform lacking the DNA binding domain, which suggests a dominant negative function, and its expression is more frequently in the CD4+ T cells from lupus patients than in healthy controls. With the hypothesis that Pbx1-d contributes to lupus development by regulating CD4+ T cell effector functions through novel mechanisms, we have generated B6.CD4-Pbx1-d Tg (Pbx1-d Tg) mice, which specifically express Pbx1-d in CD4+ T cells. These Tg mice reproduce the phenotypes of B6.Sle1a1 mice, with increased inflammatory functions of CD4+ T cells and impaired Treg cell homeostasis. Interestingly, the composition of follicular helper and regulatory T cell (Tfh and Tfr) populations, is different in the Pbx1-d Tg mice as well as the B6.Sle1.Sle2.Sle3 mice as compared with wild-type mice. Currently, we are investigating the mechanisms by which Pbx1 regulates Treg homeostasis and follicular T cell differentiation in the Pbx1-d Tg mice, as well as its role in autoimmune pathology in the B6.Sle1.Sle2.Sle3 mice.