Graphical Abstract Highlights d We identify the murine homolog of human AXL + DCs, now called transitional DCs (tDCs) d tDC development depends on Tcf4, similar to pDCs d tDCs are inefficient at IFN-I production but can efficiently activate T cells d During influenza infection, tDCs and pDCs accumulate in the lung

Phenotypic and transcriptional profiling of Treg cells at homeostasis reveals that TCR activation promotes Treg cells with an effector phenotype (eTreg) characterized by the production of IL-10 and expression of the inhibitory receptor PD-1. At homeostasis, blockade of the PD-1 pathway results in enhanced eTreg cell activity while during infection with T. gondii early IFN-γ upregulates myeloid cell expression of PD-L1 associated with reduced Treg cell populations. In infected mice, the blockade of PD-L1, complete deletion of PD-1, or lineage-specific deletion of PD-1 in Treg cells prevents loss of eTreg cells. These interventions resulted in a reduced ratio of pathogen-specific effector T cells : eTregs and increased levels of IL-10 that mitigated the development of immunopathology, but which could compromise parasite control. Thus, eTreg cell expression of PD-1 acts as a sensor to rapidly tune the pool of eTreg cells at homeostasis and during inflammatory processes.

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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.

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 Treg cells which was associated with increased eTreg proliferation, enhanced production of IL-10, and altered dendritic cell 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.