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

Abstract

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.

Keywords: CTLA-4 (cytotoxic T lymphocyte-associated antigen 4); IL-10 (Interleukin 10); PD-1 - PD-L1 axis; checkpoint blockade immunotherapy; eTreg cells; homeostatic regulation; immune suppression; treg - regulatory T cell.