Lupus susceptibility gene Pbx1 controls the development, stability, and function of regulatory T cells via Rtkn2 expression

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