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 (Tregs) have an activated phenotype associated with enhanced TCR signals and these effector Treg cells (eTregs) 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 eTreg populations, while combination blockade of both pathways had an additive effect. Mechanistically, combination blockade resulted in a reduction of suppressive phospho-SHP2 Y580 in eTreg 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 eTreg function and the ability to target these pathways in Treg cells may be useful to modulate inflammation.

Interruption of the Intratumor CD8:Treg Crosstalk Improves the Efficacy of PD-1 Immunotherapy

“…Still, there was a trend towards increased proportions of Tregs after PD-1 blockade (Fig. S1J-L), possibly due to the PD-1-mediated restriction of lymph node Treg activation at homeostasis (Pereira et al, 2023). We also observed a tendency for eTregs and activated CD44 hi CD62L -CD8 cells to accumulate after PD-1 blockade (Fig.…”

Tumour-associated macrophages: versatile players in the tumour microenvironment

“…IL-10 inhibits the production of the anticancer cytokine IFN-γ in NK cells ( Wang et al, 2021a ). TAMs in these diverse cancer types express programmed death-ligand 1 (PD-L1) ( Sumitomo et al, 2019 ; Shinchi et al, 2022 ; Xia et al, 2022 ; Elomaa et al, 2023 ), which interacts with the PD-1 receptor on T cells ( Pereira et al, 2023 ; Puig-Saus et al, 2023 ) and NK cells ( Zhou et al, 2023a ; van der Sluis et al, 2023 ), leading to their exhaustion and promoting tumour immune evasion. TAM-derived CCL22 (C-C Motif Chemokine Ligand 22) contributes to the recruitment and activation of regulatory T cells (Tregs) ( Rapp et al, 2019 ; Chen et al, 2022a ), inducing immunosuppression in TME ( Kraaij et al, 2010 ; Erlandsson et al, 2019 ).…”

Immunological mechanisms of tolerance: Central, peripheral and the role of T and B cells

“…IL-10 can activate the STAT3 signaling pathway to promote Treg development and expansion [ 33 ] and can inhibit the production of pro-inflammatory cytokines such as IL-6 and IL-12 by DCs, which in turn promotes Treg expansion and suppressive functions [ 34 , 35 ]. IL-10 also enhances Treg expansion and suppressive functions by upregulating CTLA-4 and PD-1 [ 36 ]. IL-10 also plays a role in regulating the differentiation of naive T cells into Teff cells.…”