Research ArticleGraft-Versus-Host Disease

STING differentially regulates experimental GVHD mediated by CD8 versus CD4 T cell subsets

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Science Translational Medicine  15 Jul 2020:
Vol. 12, Issue 552, eaay5006
DOI: 10.1126/scitranslmed.aay5006

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Avoiding the STING of GVHD

Stimulator of interferon genes (STING) is important for gut homeostasis and has been shown to be protective against experimental GVHD after MHC-mismatched allogeneic hematopoietic stem cell transplantation (aHSCT). In contrast, Bader et al. observed that STING promoted GVHD in mouse models of MHC-matched aHSCT. This seemingly paradoxical result was due to GVHD being driven by different types of T cells in the MHC-matched or MHC-mismatched models. Experiments were carried out to understand the importance of STING activity in different cellular compartments and immune subsets. This study, using more clinically relevant MHC-matched aHSCT models, emphasizes the importance of STING in the gut and provides guidance for potential GVHD prophylaxis.

Abstract

The stimulator of interferon genes (STING) pathway has been proposed as a key regulator of gastrointestinal homeostasis and inflammatory responses. Although STING reportedly protects against gut barrier damage and graft-versus-host disease (GVHD) after major histocompatibility complex (MHC)–mismatched allogeneic hematopoietic stem cell transplantation (aHSCT), its effect in clinically relevant MHC-matched aHSCT is unknown. Studies here demonstrate that STING signaling in nonhematopoietic cells promoted MHC-matched aHSCT–induced GVHD and that STING agonists increased type I interferon and MHC I expression in nonhematopoietic mouse intestinal organoid cultures. Moreover, mice expressing a human STING allele containing three single-nucleotide polymorphisms associated with decreased STING activity also developed reduced MHC-matched GVHD, demonstrating STING’s potential clinical importance. STING−/− recipients experienced reduced GVHD with transplant of purified donor CD8+ T cells in both MHC-matched and MHC-mismatched models, reconciling the seemingly disparate results. Further examination revealed that STING deficiency reduced the activation of donor CD8+ T cells early after transplant and promoted recipient MHC class II+ antigen-presenting cell (APC) survival. Therefore, APC persistence in STING pathway absence may account for the increased GVHD mediated by CD4+ T cells in completely mismatched recipients. In total, our findings have important implications for regulating clinical GVHD by targeting STING early after aHSCT and demonstrate that an innate immune pathway has opposing effects on the outcome of aHSCT, depending on the donor/recipient MHC disparity.

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