PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis

At homeostasis, a substantial proportion of Foxp3(+) T regulatory cells (T(regs)) have an activated phenotype associated with enhanced TCR signals and these effector T(reg) cells (eT(regs)) co-express elevated levels of PD-1 and CTLA-4. Short term in vivo blockade of the PD-1 or CTLA-4 pathways results in increased eT(reg) 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(reg) 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(reg) function and the ability to target these pathways in T(reg) cells may be useful to modulate inflammation.