Lupus susceptibility gene <i>Pbx1</i> controls the development, stability, and function of regulatory T cells via <i>Rtkn2</i> expression.

Abstract

The maintenance of regulatory T (T_reg) cells critically prevents autoimmunity. Pre-B cell leukemia transcription factor 1 (<i>Pbx1</i>) variants are associated with lupus susceptibility, particularly through the expression of a dominant negative isoform <i>Pbx1-d</i> in CD4⁺ T cells. <i>Pbx1-d</i> overexpression impaired T_reg cell homeostasis and promoted inflammatory CD4⁺ T cells. Here, we showed a high expression of <i>Pbx1</i> in human and murine T_reg cells, which is decreased in lupus patients and mice. <i>Pbx1</i> deficiency or <i>Pbx1-d</i> overexpression reduced the number, stability, and suppressive activity of T_reg cells, which increased murine responses to immunization and autoimmune induction. Mechanistically, <i>Pbx1</i> deficiency altered the expression of genes implicated in cell cycle and apoptosis in T_reg cells. Intriguingly, <i>Rtkn2</i>, a Rho-GTPase previously associated with T_reg homeostasis, was directly transactivated by Pbx1. Our results suggest that the maintenance of T_reg cell homeostasis and stability by <i>Pbx1</i> through cell cycle progression prevent the expansion of inflammatory T cells that otherwise exacerbates lupus progression in the hosts.