| The immune system is tightly controlled to mount the appropriate response to foreign threats while avoiding damage to self. T-regulatory cells (Treg) are critical in suppressing excessive immune responses to maintain immune homeostasis and prevent immunopathology. Perturbation of Treg development or function causes dysfunctional immune responses that can lead to autoimmune reactions or chronic inflammation, often contributing to cardiovascular, neurodegenerative diseases or cancers. How Tregs orchestrate this fine-tuned balance between dangerous immune responses and preservation of self and commensals is not well characterized. Furthermore, how Tregs differentiate from their naïve precursors into a multifunctional population of mature regulatory cells is not well understood. We support a model of Treg heterogeneity, in which Tregs are a qualitatively diverse population, with differences in regulation and effector mechanisms. We show that IL-1R1, IL-1R2, TNFR2, GARP and HELIOS are preferentially expressed on Tregs, and reveal different populations within the Treg subset. We also characterize a recently described subset of Tregs, which secrete the inflammatory cytokine IL-17 (Treg-Th17). We show that the differentiation of Treg-Th7 cells occurs from a discrete subset of naïve Treg precursors, both from adult and neonatal blood.;Overall, our findings suggest that Tregs are functionally heterogeneous and may also modulate innate immune responses. The expression of the IL-1 Receptors and GARP on Treg subsets suggests that these cells can sense the level of immune activation in the environment and may buffer cytokine signals to direct their own differentiation. Understanding how Treg-Th17 cells differentiate could provide insight into the development of several gut pathologies, which they are now associated with. In addition, the steady-state function of Treg-Th17 cells is unknown and opens up exciting new questions about tolerogenic host-defense strategies. The knowledge gained from our studies may have important implications for the design of therapeutic vaccines and immunotherapies for infectious diseases and cancers. |
