AUTHOR=Pereira Joseph A. , Lanzar Zachary , Clark Joseph T. , Hart Andrew P. , Douglas Bonnie B. , Shallberg Lindsey , O’Dea Keenan , Christian David A. , Hunter Christopher A. 

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

JOURNAL=Frontiers in Immunology

VOLUME=14

YEAR=2023

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2023.997376

DOI=10.3389/fimmu.2023.997376

ISSN=1664-3224

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