Faculty Collaboration Database

STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function. Cell Mol Immunol 2021 Mar;18(3):632-643

Date

01/28/2021

Pubmed ID

33500563

Pubmed Central ID

PMC8027033

DOI

10.1038/s41423-020-00611-6

Scopus ID

2-s2.0-85099750259 (requires institutional sign-in at Scopus site)   4 Citations

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.

Author List

Wu Y, Tang CA, Mealer C, Bastian D, Hanief Sofi M, Tian L, Schutt S, Choi HJ, Ticer T, Zhang M, Sui X, Huang L, Mellor AL, Hu CA, Yu XZ

Authors

Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Antigen-Presenting Cells
CD4-Positive T-Lymphocytes
CD8-Positive T-Lymphocytes
Female
Graft vs Host Disease
Hematopoietic Stem Cell Transplantation
Intestines
Macrophages
Male
Membrane Proteins
Mice
Mice, Inbred C57BL
Mice, Knockout
Transplantation, Homologous