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

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

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish (US)
Pages (from-to)632-643
Number of pages12
JournalCellular and Molecular Immunology
Volume18
Issue number3
DOIs
StatePublished - Mar 2021

Keywords

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

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology
  • Infectious Diseases

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