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STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function

Cellular & Molecular Immunology 2021年第3期18卷 632-643页

作者： Hee-Jin Choitaylor ticer Yongxia Wu Chih-Hang Anthony Tang Corey Mealer David Bastian M.Hanief Sofi Linlu Tian Steven Schutt Hee-Jin Choi taylor ticer Mengmeng Zhang Xiaohui Sui Lei Huang Andrew L.Mellor Chih-Chi Andrew Hu Xue-Zhong Yu Microbiology&Immunology Medical University of South CarolinaCharlestonSCUSA Immunology Microenvironment&Metastasis ProgramThe Wistar InstitutePhiladelphiaPAUSA Translational and Clinical Research Institute Faculty of Medical SciencesNewcastle UniversityNewcastle upon TyneUK Department of Medicine Medical University of South CarolinaCharlestonSCUSA Hollings Cancer Center Medical University of South CarolinaCharlestonSCUSA

Stimulator of interferon genes(STING)-mediated innate immune activation plays a key role in tumor-and self-DNA-elicited antitumor immunity and ***,STING can also suppress tumor immunity and *** signaling In host nonhematopoietic cells was reported to either protect against or promote graft-versus-host disease(GVHD),a major complication of allogeneic hematopoietic cell transplantation(allo-HCT).Host hematopoietic antigen-presenting cells(APCs)play key roles in donor T-cell priming during GVHD ***,how STING regulates host hematopoietic APCs after allo-HCT remains *** utilized murine models of allo-HCT to assess the role of STING in hematopoietic ***-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched *** bone marrow chimeras,we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the ***,STING on host CD11c+cells played a dominant role in suppressing allogeneic T-cell ***,STING deficiency resulted in increased survival,activation,and function of APCs,including macrophages and dendritic ***,constitutive activation of STING attenuated the survival,activation,and function of APCs isolated from STING V154M knock-in ***-deficient APCs augmented donor T-cell expansion,chemokine receptor expression,and migration into intestinal tissues,resulting in accelerated/exacerbated *** pharmacologic approaches,we demonstrated that systemic administration of a STING agonist(bis-(3'-5')-cyclic dimeric guanosine monophosphate)to recipient mice before transplantation significantly reduced GVHD *** conclusion,we revealed a novel role of STING in APC activity that dictates T-cell allogeneic responses and validated STING as a potential therapeutic target for controlling GVHD after allo-HCT.

关键词： Stimulator of interferon genes antigen-presenting cells allogeneic hematopoietic cell transplantation graft-versushost diseases hematopoietic stem-cell transplantation T cells

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