Foxp1 and Foxp4 regulate Foxp3+ nTreg generation in the thymus (P4420)

Abstract

Abstract CD4+ Foxp3+ regulatory T cells (Tregs) are fundamental for transplantation tolerance and prevention of autoimmunity. nTreg generation occurs in the thymus and requires both T cell receptor- and cytokine receptor-generated signals. Foxp1 and Foxp4 are closely related transcription factors expressed in both Tregs and conventional T cells. We sought to determine whether Foxp1 and Foxp4 have a role in nTreg development. Using a CD4Cre transgenic conditional knockout approach, we deleted both Foxp1 and Foxp4 in the T lineage. Mice conditionally deficient for both Foxp1 and Foxp4 (cDKO) have normal thymic cellularity. CD4SP and CD8SP thymocytes are present in normal ratios. CD4+Foxp3+ cells are present but express higher levels of receptors for IL-2 and IL-7. Markers of activation CD44, CD69, and GITR are also found at elevated levels on the cell surface. In the competitive setting of mixed bone marrow chimeras, there is a significant reduction in cDKO-derived chimerism in the Foxp3+ nTreg population. The competitive disadvantage occurs despite expression of the high affinity IL-2 receptor alpha chain, CD25. Together, these results suggest that Foxp1 and Foxp4 are necessary for the normal generation of nTreg cells. Ongoing experiments to understand the underlying molecular basis of these findings will be discussed.