Natural killer (NK) cells have the ability to mediate both bone marrow rejection and promote engraftment,as well as the ability to elicit potent anti-tumor effects.However the clinical results for these processes are ...Natural killer (NK) cells have the ability to mediate both bone marrow rejection and promote engraftment,as well as the ability to elicit potent anti-tumor effects.However the clinical results for these processes are still elusive.Greater understanding of NK cell biology,from activating and inhibitory receptor functions to the role of NK cells in allogeneic transplantation,needs to be appreciated in order to draw out the clinical potential of NK cells.Mechanisms of bone marrow cell (BMC) rejection are known to be dependant on inhibitory receptors specific for major histocompatibility complex (MHC) molecules and on activating receptors that have many potential ligands.The modulation of activating and inhibitory receptors may hold the key to clinical success involving NK cells.Pre-clinical studies in mice have shown that different combinations of activating and inhibitory receptors on NK cells can reduce graft-versus-host disease (GVHD),promote engraftment,and provide superior graft-versus-tumor (GVT) responses.Recent clinical data have shown that the use of KIR-ligand incompatibility produces tremendous graft-versus-leukemia effect in patients with acute myeloid leukemia at high risk of relapse.This review will attempt to be a synthesis of current knowledge concerning NK cells,their involvement in BMT,and their use as an immunotherapy for cancer and other hematologic malignancies.Cellular & Molecular Immunology.2004;1(1):12-21.展开更多
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.Previou...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.展开更多
Whole-genome sequences provide massive amounts of data that can illuminate many aspects of a species’biology and evolutionary history,as well as valuable information for conservation planning.This is particularly imp...Whole-genome sequences provide massive amounts of data that can illuminate many aspects of a species’biology and evolutionary history,as well as valuable information for conservation planning.This is particularly important for large carnivores,whose large area requirements and typical low densities make them prone to undergo rapid genetic erosion(e.g.accumulation of runs of homozygosity,Diez del Molino et al.,2018;Leroy et al.,2018)in the face of habitat loss and human persecution.One such species is the jaguar(Pan-thera onca),the largest extant felid in the Americas,whose range has already declined by>50%and some of whose remaining popu-lations have been severely impacted by human-induced habitat frag-mentation(De La Torre et al.,2018).展开更多
文摘Natural killer (NK) cells have the ability to mediate both bone marrow rejection and promote engraftment,as well as the ability to elicit potent anti-tumor effects.However the clinical results for these processes are still elusive.Greater understanding of NK cell biology,from activating and inhibitory receptor functions to the role of NK cells in allogeneic transplantation,needs to be appreciated in order to draw out the clinical potential of NK cells.Mechanisms of bone marrow cell (BMC) rejection are known to be dependant on inhibitory receptors specific for major histocompatibility complex (MHC) molecules and on activating receptors that have many potential ligands.The modulation of activating and inhibitory receptors may hold the key to clinical success involving NK cells.Pre-clinical studies in mice have shown that different combinations of activating and inhibitory receptors on NK cells can reduce graft-versus-host disease (GVHD),promote engraftment,and provide superior graft-versus-tumor (GVT) responses.Recent clinical data have shown that the use of KIR-ligand incompatibility produces tremendous graft-versus-leukemia effect in patients with acute myeloid leukemia at high risk of relapse.This review will attempt to be a synthesis of current knowledge concerning NK cells,their involvement in BMT,and their use as an immunotherapy for cancer and other hematologic malignancies.Cellular & Molecular Immunology.2004;1(1):12-21.
基金This work was supported by grants from the National Institutes of Health,National Institute of Allergy and Infectious Diseases P01 AI056299,R37 AI034495(BRB),and R01 AI091627(IM)and the National Heart,Lung,and Blood Institute R01 HL56067(BRB)This work was supported in part using the resources of the Center for Innovative Technology at Vanderbilt University.GT was supported by a Canadian Institutes of Health Research(CIHR)fellowship.
文摘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.
基金supported by CNPq/BrazilINCT-EECBio/BrazilCAPES/Brazil。
文摘Whole-genome sequences provide massive amounts of data that can illuminate many aspects of a species’biology and evolutionary history,as well as valuable information for conservation planning.This is particularly important for large carnivores,whose large area requirements and typical low densities make them prone to undergo rapid genetic erosion(e.g.accumulation of runs of homozygosity,Diez del Molino et al.,2018;Leroy et al.,2018)in the face of habitat loss and human persecution.One such species is the jaguar(Pan-thera onca),the largest extant felid in the Americas,whose range has already declined by>50%and some of whose remaining popu-lations have been severely impacted by human-induced habitat frag-mentation(De La Torre et al.,2018).
