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

Abstract

Stimulator of interferon genes (STING)-mediated innate immune activation plays a key role in tumor- and self-DNA-elicited antitumor immunity and autoimmunity. However, STING can also suppress tumor immunity and autoimmunity. STING 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 initiation. However, how STING regulates host hematopoietic APCs after allo-HCT remains unknown. We utilized murine models of allo-HCT to assess the role of STING in hematopoietic APCs. STING-deficient recipients developed more severe GVHD after major histocompatibility complex-mismatched allo-HCT. Using bone marrow chimeras, we found that STING deficiency in host hematopoietic cells was primarily responsible for exacerbating the disease. Furthermore, STING on host CD11c+ cells played a dominant role in suppressing allogeneic T-cell responses. Mechanistically, STING deficiency resulted in increased survival, activation, and function of APCs, including macrophages and dendritic cells. Consistently, constitutive activation of STING attenuated the survival, activation, and function of APCs isolated from STING V154M knock-in mice. STING-deficient APCs augmented donor T-cell expansion, chemokine receptor expression, and migration into intestinal tissues, resulting in accelerated/exacerbated GVHD. Using 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 mortality. In 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.

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Acknowledgements

We appreciate the technical support provided by the Department of Lab Animal Research (DLAR) and the Flow Cytometry Core at MUSC. This work was supported in part by the Hollings Cancer Center Fellowship (to Y.W.), NIH Grant R01CA163910 (to C.-C.A.H.), and NIH R01s AI118305, HL137373, and HL140953 (to X.-Z.Y.).

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Y.W. designed and performed the research, collected, analyzed, and interpreted the data, and drafted and revised the paper; C.-H.A.T. generated the STINGflox and STING V154M mice; C.M. performed the research, collected and analyzed the data, and edited the paper; D.B., M.H.S., L.T., S.S., H.-J.C., T.T., and M.Z. assisted in collecting data and editing the paper; L.H. and A.L.M. interpreted the data and edited the paper; and C.-C.A.H. and X.-Z.Y. designed the research, interpreted the data, and revised the paper.

Corresponding authors

Correspondence to Yongxia Wu or Chih-Chi Andrew Hu or Xue-Zhong Yu.

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The authors declare no competing interests.

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Wu, Y., Tang, CH.A., Mealer, C. et al. STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function. Cell Mol Immunol 18, 632–643 (2021). https://doi.org/10.1038/s41423-020-00611-6

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Keywords

  • Stimulator of interferon genes
  • antigen-presenting cells
  • allogeneic hematopoietic cell transplantation
  • graft-versus-host diseases
  • hematopoietic stem-cell transplantation
  • T cells

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