Gfi1 couples maturation of DP thymocytes and generation of nTreg cells (P4418)

Abstract

Abstract Double-positive (DP) thymocytes respond to intrathymic TCR signaling by undergoing positive selection and lineage differentiation. Concomitant with these well-characterized events is the acquisition of mature T-cell gene-expression programs, notably the upregulation of effector molecules that are essential for their proper survival and trafficking, a process that is much less understood. nTreg cells also develop from immature thymocytes, but how their development is linked to the thymocyte maturation remains unclear. Here we report that Gfi1 has a central role in coupling DP cell maturation and thymic generation of nTreg cells. Using a conditional Gfi1 deletion system, we observed that specific ablation of Gfi1 in DP cells led to premature expression of mature effector genes and transcription factors, thereby facilitating developmental maturation. Associated with this “expedited” maturation of DP cells was expansion of nTreg cells. Mechanistically, we identified that elevated IL-2 signaling in the absence of Gfi1 drove the expansion of nTreg cells via a non-cell-autonomous mechanism. Finally, we provide evidence that deficiency of Gfi1 dampened anti-tumor immunity. Our results establish a Gfi1-dependent mechanism that actively maintains DP cell fate for proper developmental maturation and generation of nTreg cells.