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.