CD4⁺ regulatory T cells (Tregs) control Th17 responses in a Stat3-dependent manner. This study shows that Tregs suppress pathogenic Th17 responses in mice, and this suppression is lost when Stat3 is specifically ablated in Tregs, leading to fatal intestinal inflammation. The findings suggest that Tregs adapt to their environment by using distinct effector response-specific suppression mechanisms upon activation of STAT proteins that direct the corresponding immune response. The vertebrate immune system defends against different pathogens by activating specific immune responses. Intracellular pathogens induce Th1 responses, while parasitic helminths induce Th2 cytokine production. In contrast, pathogenic yeast, fungi, and extracellular bacteria elicit highly inflammatory Th17 responses associated with the production of interleukins (IL)-17, -22, -23, and granulocyte recruitment. The commitment of naive T cells to these effector lineages is influenced by environmental cues, particularly cytokines. Cytokine receptor signaling activates the STAT family of transcription factors. Uncontrolled STAT activation can lead to various immune-mediated diseases. For example, activation of Stat3 in response to the pro-inflammatory cytokine IL-6 in combination with transforming growth factor-β (TGF-β) leads to increased expression of orphan nuclear receptors RORγ and RORα, signature transcription factors for Th17 cells. Treg cells act 'in-trans' to suppress immune responses to self and commensal microbiota, and to limit pathology associated with immune responses to infection. The differentiation and maintenance of suppressive Tregs require expression of the X-chromosome-encoded forkhead transcription factor Foxp3. Mutations in Foxp3 result in a fatal immune disorder characterized by uncontrolled T cell proliferation and drastically elevated production of Th1 and Th2 cytokines, suggesting that Treg-mediated suppression is involved in controlling these responses. In contrast, Treg-mediated control of Th17 responses remains an unanswered question. Recent reports suggest that Th17 and peripherally induced Tregs represent competing fates of naive T cell differentiation, with the lineage choice determined by the relative amounts of IL-6 and TGF-β. Therefore, Tregs might limit Th17 differentiation by "stealing" common precursors. A block in Th17 differentiation in IL-6 deficient mice correlates with an increase in Treg numbers. We hypothesized that analogous to effector T cell differentiation, Tregs suppress a particular type of immune response by activating a distinct STAT family member in response to its cytokine microenvironment. We explored whether activation of Stat3 endows Tregs with the ability to suppress Th17 responses because Stat3 is a key factor in the initiation of Th17 differentiation. Using co-immunoprecipitation and western blot analysis, we found that in Tregs, Foxp3 was associated with the transcriptionally active, phosphorylated form of Stat3. StatCD4⁺ regulatory T cells (Tregs) control Th17 responses in a Stat3-dependent manner. This study shows that Tregs suppress pathogenic Th17 responses in mice, and this suppression is lost when Stat3 is specifically ablated in Tregs, leading to fatal intestinal inflammation. The findings suggest that Tregs adapt to their environment by using distinct effector response-specific suppression mechanisms upon activation of STAT proteins that direct the corresponding immune response. The vertebrate immune system defends against different pathogens by activating specific immune responses. Intracellular pathogens induce Th1 responses, while parasitic helminths induce Th2 cytokine production. In contrast, pathogenic yeast, fungi, and extracellular bacteria elicit highly inflammatory Th17 responses associated with the production of interleukins (IL)-17, -22, -23, and granulocyte recruitment. The commitment of naive T cells to these effector lineages is influenced by environmental cues, particularly cytokines. Cytokine receptor signaling activates the STAT family of transcription factors. Uncontrolled STAT activation can lead to various immune-mediated diseases. For example, activation of Stat3 in response to the pro-inflammatory cytokine IL-6 in combination with transforming growth factor-β (TGF-β) leads to increased expression of orphan nuclear receptors RORγ and RORα, signature transcription factors for Th17 cells. Treg cells act 'in-trans' to suppress immune responses to self and commensal microbiota, and to limit pathology associated with immune responses to infection. The differentiation and maintenance of suppressive Tregs require expression of the X-chromosome-encoded forkhead transcription factor Foxp3. Mutations in Foxp3 result in a fatal immune disorder characterized by uncontrolled T cell proliferation and drastically elevated production of Th1 and Th2 cytokines, suggesting that Treg-mediated suppression is involved in controlling these responses. In contrast, Treg-mediated control of Th17 responses remains an unanswered question. Recent reports suggest that Th17 and peripherally induced Tregs represent competing fates of naive T cell differentiation, with the lineage choice determined by the relative amounts of IL-6 and TGF-β. Therefore, Tregs might limit Th17 differentiation by "stealing" common precursors. A block in Th17 differentiation in IL-6 deficient mice correlates with an increase in Treg numbers. We hypothesized that analogous to effector T cell differentiation, Tregs suppress a particular type of immune response by activating a distinct STAT family member in response to its cytokine microenvironment. We explored whether activation of Stat3 endows Tregs with the ability to suppress Th17 responses because Stat3 is a key factor in the initiation of Th17 differentiation. Using co-immunoprecipitation and western blot analysis, we found that in Tregs, Foxp3 was associated with the transcriptionally active, phosphorylated form of Stat3. Stat