Retinoic acid signaling acts as a rheostat to balance Treg function

Regulatory T cells(Tregs)promote immune homeostasis by maintaining self-tolerance and regulating inflammatory responses.Under certain inflammatory conditions,Tregs can lose their lineage stability and function.Previous studies have reported that ex vivo exposure to retinoic acid(RA)enhances Treg function and stability.However,it is unknown how RA receptor signaling in Tregs influences these processes in vivo.Herein,we employed mouse models in which RA signaling is silenced by the expression of the dominant negative receptor(DN)RARαin all T cells.Despite the fact that DNRARαconventional T cells are hypofunctional,Tregs had increased CD25 expression,STAT5 pathway activation,mTORC1 signaling and supersuppressor function.Furthermore,DNRARαTregs had increased inhibitory molecule expression,amino acid transporter expression,and metabolic fitness and decreased antiapoptotic proteins.Supersuppressor function was observed when wild-type mice were treated with a pharmacologic pan-RAR antagonist.Unexpectedly,Treg-specific expression of DNRARαresulted in distinct phenotypes,such that a single allele of DNRARαin Tregs heightened their suppressive function,and biallelic expression led to loss of suppression and autoimmunity.The loss of Treg function was not cell intrinsic,as Tregs that developed in a noninflammatory milieu in chimeric mice reconstituted with DNRARαand wild-type bone marrow maintained the enhanced suppressive capacity.Fate mapping suggested that maintaining Treg stability in an inflammatory milieu requires RA signaling.Our findings indicate that RA signaling acts as a rheostat to balance Treg function in inflammatory and noninflammatory conditions in a dose-dependent manner.

The role of VISTA in the tumor microenvironment

V-domain Ig Suppressor of T cell Activation(VISTA)is a negative immune checkpoint that is expressed on multiple immune cell subsets and has been characterized in T cells,macrophages,and myeloid-derived suppressor cells.As the only immune checkpoint expressed on naïve T cells,VISTA contributes to the maintenance of T cell quiescence and tolerance.VISTA also regulates multiple myeloid cell activities such as chemotaxis,differentiation,and migration.In the context of cancer,antagonistic monoclonal antibody targeting of VISTA has been shown to aid anti-tumor immunity.Furthermore,combination therapies that include other immune checkpoints such as PD-1 or CTLA-4 with VISTA blockade may enhance therapeutic efficacy in a variety of cancers.Combination therapy may help overcome adaptive resistance to individual checkpoint therapies,thereby improving patient outcomes and survival.Here,we summarize the role of VISTA in myeloid cells and T cells within the tumor microenvironment.We discuss the proposed counter-receptors for VISTA,VISTA antibodies currently in development,and the potential for combination therapies with checkpoint inhibitors such as PD-1 and CTLA-4.