Gfi1

Regulatory T cells (T reg), defined by the expression of the transcription factor Foxp3, are crucial for immunological self-tolerance and homeostasis. 1 T reg cells are mainly developed in the thymus as natural T reg cells (nT reg), which can be best depicted by a 2-step model. The initial signals from the high-affinity T-cell receptor (TCR) and CD28 co-stimulation lead to the generation of a precursor population with enhanced cytokine responsiveness , which then responds to signals from γc-dependent cytokines, especially IL-2 for full induction of Foxp3 expression. 2 Consistent with the importance of TCR and co-stimulatory signals for nT reg development, several transcription factors downstream of TCR/CD28 have been implicated in Foxp3 expression 2. For instance, among TCR-activated NFκB members, c-Rel has a crucial role in Foxp3 induction by binding to an intronic conserved noncoding sequence (CNS) in the Foxp3 locus, known as Foxp3-CNS3. 2 Concurrent with transcriptional activation of Foxp3 expression, TCR stimulation also leads to epigenetic modification by establishing a T reg-specific CpG hypo-methylation pattern in Foxp3-CNS2, as well as in other T reg signature genes. 3 Both transcriptional activation of Foxp3 expression and establishment of T reg-specific epigenetic modifications are required for a full developmental and suppressive program of nT reg cells. Aside from TCR/ CD28 stimulation, IL-2 directly contributes to Foxp3 transcription by activating Stat5, and thus is intimately linked to nT reg development. 2 IL-2 is also required for functional programming and expansion of nT reg cells during thymic development. 4 While remarkable advances have been made in deciphering TCR-and IL-2-induced intrinsic events in nT reg development , how the production of extrinsic signals such as IL-2 is controlled remains poorly understood. We addressed this issue by focusing on growth factor independent 1 (Gfi1), a transcription repressor important for immune and hematopoietic cell development and function. Since Gfi1 has been implicated in early thymocyte development, 5 we utilized a mouse genetic model with T cell-specific deletion of Gfi1 via CD4-Cre (Gfi1 CD4-Cre) to circumvent the early developmental defects associated with germ-line deletion of Gfi1. We identified a previously unappreciated mechanism in which Gfi1 exerts a non-cell-autonomous effect to curtail nT reg development by inhibiting IL-2 production from conventional T cells 6 (Fig. 1). Combining pharmacological blockade of IL-2 signaling and genetic deletion of Il2, we showed that excessive IL-2 production in Gfi1 CD4-Cre mice underlined the augmented nT reg development in Gfi1 CD4-Cre mice. …