TY - JOUR
T1 - STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function
AU - Wu, Yongxia
AU - Tang, Chih Hang Anthony
AU - Mealer, Corey
AU - Bastian, David
AU - Hanief Sofi, M.
AU - Tian, Linlu
AU - Schutt, Steven
AU - Choi, Hee Jin
AU - Ticer, Taylor
AU - Zhang, Mengmeng
AU - Sui, Xiaohui
AU - Huang, Lei
AU - Mellor, Andrew L.
AU - Hu, Chih Chi Andrew
AU - Yu, Xue Zhong
N1 - Publisher Copyright:
© 2021, The Author(s), under exclusive licence to CSI and USTC.
PY - 2021/3
Y1 - 2021/3
N2 - 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.
AB - 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.
KW - Stimulator of interferon genes
KW - T cells
KW - allogeneic hematopoietic cell transplantation
KW - antigen-presenting cells
KW - graft-versus-host diseases
KW - hematopoietic stem-cell transplantation
UR - http://www.scopus.com/inward/record.url?scp=85099750259&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85099750259&partnerID=8YFLogxK
U2 - 10.1038/s41423-020-00611-6
DO - 10.1038/s41423-020-00611-6
M3 - Article
C2 - 33500563
AN - SCOPUS:85099750259
SN - 1672-7681
VL - 18
SP - 632
EP - 643
JO - Cellular and Molecular Immunology
JF - Cellular and Molecular Immunology
IS - 3
ER -