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

Cellular & Molecular Immunology volume 18, pages 632–643 (2021)Cite this article

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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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References

  1. Ishikawa, H. & Barber, G. N. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature 455, 674–678 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Motwani, M., Pesiridis, S. & Fitzgerald, K. A. DNA sensing by the cGAS-STING pathway in health and disease. Nat. Rev. Genet. 20, 657–674 (2019).

    Article  CAS  PubMed  Google Scholar 

  3. Liu, Y. et al. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371, 507–518 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Ahn, J., Gutman, D., Saijo, S. & Barber, G. N. STING manifests self DNA-dependent inflammatory disease. Proc. Natl Acad. Sci. 109, 19386–19391 (2012).

    Article  CAS  PubMed  Google Scholar 

  5. Woo, S.-R. et al. STING-dependent cytosolic DNA sensing mediates innate immune recognition of immunogenic tumors. Immunity 41, 830–842 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kwon, J. & Bakhoum, S. F. The cytosolic DNA-sensing cGAS–STING pathway in cancer. Cancer Discov. 10, 26–39 (2020).

    Article  CAS  PubMed  Google Scholar 

  7. Perkey, E. & Maillard, I. New Insights into graft-versus-host disease and graft rejection. Annu. Rev. Pathol. 13, 219–245 (2018).

    Article  CAS  PubMed  Google Scholar 

  8. Zeiser, R. & Blazar, B. R. Acute graft-versus-host disease—biologic process, prevention, and therapy. N. Engl. J. Med. 377, 2167–2179 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Bader, C. S. et al. STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets. Sci. Transl. Med. 12 https://doi.org/10.1126/scitranslmed.aay5006 (2020).

  10. Fischer, J. C. et al. RIG-I/MAVS and STING signaling promote gut integrity during irradiation- and immune-mediated tissue injury. Sci. Transl. Med. 9 https://doi.org/10.1126/scitranslmed.aag2513 (2017).

  11. Koyama, M. & Hill, G. R. Alloantigen presentation and graft-versus-host disease: fuel for the fire. Blood 127, 2963–2970 (2016).

    Article  CAS  PubMed  Google Scholar 

  12. Tang, C. A. et al. STING regulates BCR signaling in normal and malignant B cells. Cell. Mol. Immunol. https://doi.org/10.1038/s41423-020-00552-0 (2020).

  13. Fredricks, D. N. The gut microbiota and graft-versus-host disease. J. Clin. Investig. 129, 1808–1817 (2019).

    Article  PubMed  Google Scholar 

  14. Cerboni, S. et al. Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes. J. Exp. Med. 214, 1769–1785 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Gulen, M. F. et al. Signalling strength determines proapoptotic functions of STING. Nat. Commun. 8, 1–10 (2017).

    Article  CAS  Google Scholar 

  16. Koyama, M. et al. Recipient nonhematopoietic antigen-presenting cells are sufficient to induce lethal acute graft-versus-host disease. Nat. Med. 18, 135–142 (2011).

    Article  PubMed  Google Scholar 

  17. Koyama, M. et al. MHC class II antigen presentation by the intestinal epithelium initiates graft-versus-host disease and is influenced by the microbiota. Immunity 51, 885–898.e887 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Zhu, Y. et al. STING: a master regulator in the cancer-immunity cycle. Mol. Cancer 18, 152 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Hume, D. A. Macrophages as APC and the dendritic cell myth. J. Immunol. 181, 5829–5835 (2008).

    Article  CAS  PubMed  Google Scholar 

  20. Arnold, I. C. et al. CD11c+ monocyte/macrophages promote chronic Helicobacter hepaticus-induced intestinal inflammation through the production of IL-23. Mucosal Immunol. 9, 352–363 (2016).

    Article  CAS  PubMed  Google Scholar 

  21. Koyama, M. & Hill, G. R. The primacy of gastrointestinal tract antigen-presenting cells in lethal graft-versus-host disease. Blood 134, 2139–2148 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  22. Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Zhang, Y. et al. APCs in the liver and spleen recruit activated allogeneic CD8+ T cells to elicit hepatic graft-versus-host disease. J. Immunol. 169, 7111–7118 (2002).

    Article  CAS  PubMed  Google Scholar 

  24. Schwab, L. et al. Neutrophil granulocytes recruited upon translocation of intestinal bacteria enhance graft-versus-host disease via tissue damage. Nat. Med. 20, 648–654 (2014).

    Article  CAS  PubMed  Google Scholar 

  25. Garcia, J. A. et al. Regulation of adaptive immunity by the fractalkine receptor during autoimmune inflammation. J. Immunol. 191, 1063–1072 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Wysocki, C. A., Panoskaltsis-Mortari, A., Blazar, B. R. & Serody, J. S. Leukocyte migration and graft-versus-host disease. Blood 105, 4191–4199 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Zhou, V. et al. A colitogenic memory CD4+ T cell population mediates gastrointestinal graft-versus-host disease. J. Clin. Investig. 126, 3541–3555 (2016).

    Article  PubMed  Google Scholar 

  28. Burdette, D. L. et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature 478, 515–518 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Karaolis, D. K. et al. Bacterial c-di-GMP is an immunostimulatory molecule. J. Immunol. 178, 2171–2181 (2007).

    Article  CAS  PubMed  Google Scholar 

  30. Gall, A. et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36, 120–131 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Larkin, B. et al. Cutting edge: activation of STING in T cells induces type I IFN responses and cell death. J. Immunol. 199, 397–402 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Liang, D. et al. Activated STING enhances Tregs infiltration in the HPV-related carcinogenesis of tongue squamous cells via the c-jun/CCL22 signal. Biochim. Biophys. Acta 1852, 2494–2503 (2015).

    Article  PubMed  Google Scholar 

  33. Lemos, H. et al. STING promotes the growth of tumors characterized by low antigenicity via IDO activation. Cancer Res. 76, 2076–2081 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Sharma, S. et al. Suppression of systemic autoimmunity by the innate immune adaptor STING. Proc. Natl Acad. Sci. 112, E710–E717 (2015).

    Article  CAS  PubMed  Google Scholar 

  35. Gaidt, M. M. et al. The DNA inflammasome in human myeloid cells is initiated by a STING-cell death program upstream of NLRP3. Cell 171, 1110–1124.e1118 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Jeremiah, N. et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J. Clin. Investig. 124, 5516–5520 (2014).

    Article  PubMed  Google Scholar 

  37. Warner, J. D. et al. STING-associated vasculopathy develops independently of IRF3 in mice. J. Exp. Med. 214, 3279–3292 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Bennion, B. G. et al. A human gain-of-function STING mutation causes immunodeficiency and gammaherpesvirus-induced pulmonary fibrosis in mice. J. Virol. 93, e01806-18 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Crow, M. K., Olferiev, M., Kirou, K. A. & Type, I. Interferons in autoimmune disease. Annu. Rev. Pathol. 14, 369–393 (2019).

    Article  CAS  PubMed  Google Scholar 

  40. Kotredes, K. P., Thomas, B. & Gamero, A. M. The protective role of type I interferons in the gastrointestinal tract. Front. Immunol. 8, 410 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  41. Petrasek, J. et al. STING-IRF3 pathway links endoplasmic reticulum stress with hepatocyte apoptosis in early alcoholic liver disease. Proc. Natl Acad. Sci. USA 110, 16544–16549 (2013).

    Article  CAS  PubMed  Google Scholar 

  42. Tang, C.-H. A. et al. Agonist-mediated activation of STING induces apoptosis in malignant B cells. Cancer Res. 76, 2137–2152 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Huang, L. et al. Cutting edge: DNA sensing via the STING adaptor in myeloid dendritic cells induces potent tolerogenic responses. J. Immunol. 191, 3509–3513 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Jasperson, L. K. et al. Inducing the tryptophan catabolic pathway, indoleamine 2, 3-dioxygenase (IDO), for suppression of graft-versus-host disease (GVHD) lethality. Blood 114, 5062–5070 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  45. Galleu, A. et al. Apoptosis in mesenchymal stromal cells induces in vivo recipient-mediated immunomodulation. Sci. Transl. Med. 9 https://doi.org/10.1126/scitranslmed.aam7828 (2017).

  46. Koyama, M. et al. MHC class II antigen presentation by the intestinal epithelium initiates graft-versus-host disease and is influenced by the microbiota. Immunity 51, 885–898. e887 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Hashimoto, D. et al. Pretransplant CSF-1 therapy expands recipient macrophages and ameliorates GVHD after allogeneic hematopoietic cell transplantation. J. Exp. Med. 208, 1069–1082 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Duffner, U. A. et al. Host dendritic cells alone are sufficient to initiate acute graft-versus-host disease. J. Immunol. 172, 7393–7398 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Weber, M. et al. Host-derived CD8(+) dendritic cells protect against acute graft-versus-host disease after experimental allogeneic bone marrow transplantation. Biol. Blood Marrow Transplant. 20, 1696–1704 (2014).

    Article  CAS  PubMed  Google Scholar 

  50. Hadeiba, H. et al. CCR9 expression defines tolerogenic plasmacytoid dendritic cells able to suppress acute graft-versus-host disease. Nat. Immunol. 9, 1253–1260 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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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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Authors and Affiliations

  1. Microbiology & Immunology, Medical University of South Carolina, Charleston, SC, USA

    Yongxia Wu, Corey Mealer, David Bastian, M. Hanief Sofi, Linlu Tian, Steven Schutt, Hee-Jin Choi, Taylor Ticer, Mengmeng Zhang, Xiaohui Sui & Xue-Zhong Yu

  2. Immunology, Microenvironment & Metastasis Program, The Wistar Institute, Philadelphia, PA, USA

    Chih-Hang Anthony Tang & Chih-Chi Andrew Hu

  3. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK

    Lei Huang & Andrew L. Mellor

  4. Department of Medicine, Medical University of South Carolina, Charleston, SC, USA

    Xue-Zhong Yu

  5. Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA

    Xue-Zhong Yu

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Contributions

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.

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

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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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