Regulatory T cells (Tregs) are a specialized subset of CD4+ T cells defined by expression of the transcription factor Foxp3. These cells have key roles in preventing the development of autoimmunity and also restricting the magnitude of inflammatory responses to commensal or infectious organisms – mitigating immunopathology. In the context of infection, Treg cells are important in limiting excessive pathology, however Treg-mediated immunosuppression can also blunt protective immunity and lead to pathogen persistence. Consequently, there are multiple mechanisms that regulate Treg cell populations at homeostasis as well as during inflammation. Even at homeostasis, external factors such as antigen availability, cytokine milieu, and tissue location allow Treg cells to adopt different phenotypes that allow them to regulate different classes of inflammation. The studies presented here focus on the role of the inhibitory receptors cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and program death receptor-1 (PD-1), on the regulation of Treg cells at homeostasis and during inflammatory challenges like primary infection. In this work, PD-1 has been identified as a cell intrinsic pathway that tunes Treg cell populations at homeostasis and during systemic inflammation associated with infection, while CTLA-4 provides additive control to effector Treg proliferation and suppressive potential homeostatically. Additionally, this work includes data describing potential pathways to target specific Treg-subsets using novel engineered IL-2 mutein constructs. These findings establish that inhibitory receptors like CTLA-4 and PD-1 are constitutive regulators of a subset of highly activated effector Treg cells that dynamically regulate this population, while receptor-specific IL-2 signaling may encourage the growth and development of central memory Treg cells. Together, these studies provide insight into new strategies to modulate Treg cells that are relevant to the development of immunotherapies for cancer and autoimmunity.