PD-1 and CTLA-4 exert additive control of effector regulatory T cells at homeostasis
Joseph A. Pereira, Zachary Lanzar, Joseph T. Clark, Andrew Hart, Bonnie Douglas, Lindsey A. Shallberg, Keenan M. O’Dea, David A. Christian, Christopher A. Hunter
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.