STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function
| العنوان: | STING negatively regulates allogeneic T-cell responses by constraining antigen-presenting cell function |
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| المؤلفون: | Lei Huang, Mengmeng Zhang, Corey Mealer, Xue-Zhong Yu, Taylor Ticer, Hee-Jin Choi, Steven Schutt, Chih-Hang Anthony Tang, Chih-Chi Andrew Hu, M. Hanief Sofi, Yongxia Wu, Andrew L. Mellor, Xiaohui Sui, David Bastian, Linlu Tian |
| المصدر: | Cell Mol Immunol |
| بيانات النشر: | Springer Science and Business Media LLC, 2021. |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | CD4-Positive T-Lymphocytes, Male, 0301 basic medicine, medicine.medical_treatment, T cell, Immunology, Antigen-Presenting Cells, Graft vs Host Disease, Hematopoietic stem cell transplantation, CD8-Positive T-Lymphocytes, medicine.disease_cause, Article, Autoimmunity, Mice, 03 medical and health sciences, 0302 clinical medicine, Animals, Transplantation, Homologous, Immunology and Allergy, Medicine, Antigen-presenting cell, Mice, Knockout, Innate immune system, business.industry, Macrophages, Hematopoietic Stem Cell Transplantation, Membrane Proteins, eye diseases, Intestines, Mice, Inbred C57BL, Transplantation, Sting, surgical procedures, operative, 030104 developmental biology, Infectious Diseases, medicine.anatomical_structure, Stimulator of interferon genes, Female, business, 030215 immunology |
| الوصف: | 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. |
| تدمد: | 2042-0226 1672-7681 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::0b236faa7b838dff1b370b8a6e7634b5 https://doi.org/10.1038/s41423-020-00611-6 |
| حقوق: | OPEN |
| رقم الأكسشن: | edsair.doi.dedup.....0b236faa7b838dff1b370b8a6e7634b5 |
| قاعدة البيانات: | OpenAIRE |
Find this article in full text from Springer Verlag. | تدمد: | 20420226 16727681 |
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