Inhibitory role of the transcription repressor Gfi1 in the generation of thymus-derived regulatory T cells

Foxp3⁺ regulatory T (T_reg) cells are essential for the maintenance of self-tolerance and immune homeostasis. The majority of T _reg cells is generated in the thymus as a specific subset of CD4 ⁺ T cells, known as thymus-derived or natural T_reg (nT_reg) cells, in response to signals from T-cell receptors, costimulatory molecules, and cytokines. Recent studies have identified intracellular signaling and transcriptional pathways that link these signals to Foxp3 induction, but how the production of these extrinsic factors is controlled remains poorly understood. Here, we report that the transcription repressor growth factor independent 1 (Gfi1) has a key inhibitory role in the generation of nT_reg cells by a noncell-autonomous mechanism. T cell-specific deletion of Gfi1 results in aberrant expansion of thymic nT_reg cells and increased production of cytokines. In particular, IL-2 overproduction plays an important role in driving the expansion of nT_reg cells. In contrast, although Gfi1 deficiency elevated thymocyte apoptosis, Gfi1 repressed nT_reg generation independently of its prosurvival effect. Consistent with an inhibitory role of Gfi1 in this process, loss of Gfi1 dampens antitumor immunity. These data point to a previously unrecognized extrinsic control mechanism that negatively shapes thymic generation of nT_reg cells.