At homeostasis, a substantial proportion of Foxp3 T regulatory cells (T) have an activated phenotype associated with enhanced TCR signals and these effector T cells (eT) co-express elevated levels of PD-1 and CTLA-4. Short term blockade of the PD-1 or CTLA-4 pathways results in increased eT populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in eT cells which was associated with increased proliferation, enhanced production of IL-10, and reduced dendritic cell and macrophage expression of CD80 and MHC-II. Thus, at homeostasis, PD-1 and CTLA-4 function additively to regulate eT function and the ability to target these pathways in T cells may be useful to modulate inflammation.