The ability to generate rapid robust immune responses to a wide variety of targets enables mammalian survival in a world teeming with microbes. Yet, keeping such responses in check is essential for avoiding chronic inflammatory diseases. This dichotomy is exemplified by the function of the intestinal immune system, which is charged with detecting and clearing pathogens without responding excessively to the large microbial ecosystem that normally inhabits this organ in a mutually beneficial manner. Intestinal CD4+ T cells are integral for mediating host homeostasis. However, when unchecked, these cells drive and sustain chronic immune-mediated inflammatory diseases, particularly inflammatory bowel disease (IBD).
1CD4+ T cells are functionally grouped as effector and regulatory cells (Treg). Intestinal CD4+ effector T cells such as Th1 produce proinflammatory cytokine interferon (IFN)-γ to protect host against pathogens, whereas T-reg generate anti-inflammatory cytokines to prevent excessive inflammation that might otherwise lead to IBD.
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Dissecting the heterogeneity in T-cell mediated inflammation in IBD.
Cells. 2020; 9: 110
2Regulation of IFN-γ secreting Th1 (IFN-γ+Th1) cells is tightly controlled both intrinsic and extrinsic. Extrinsically, T-reg and myeloid cells are keys to suppressing Th1 by producing interleukin (IL)-10.
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Cytokine networks and T-cell subsets in inflammatory bowel diseases.
Inflamm Bowel Dis. 2016; 22: 1157-1167
3However, environmental cues that control the intrinsic switching from IFN-γ+Th1 to IL-10+IFN-γ+Th1 cells during Th1 lineage differentiation remain poorly understood.
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Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine.
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A report by Cong and colleagues in this issue of Cellular and Molecular Gastroenterology and Hepatology reports that the stimulator of interferon genes (STING) protein plays a key role in reducing the pro-inflammatory activity of Th1 cells.
4Specifically, their work demonstrates that activation of STING causes Th1 cells to reduce their production of pro-inflammatory cytokines such as IL-6 and tumor necrosis factor (TNF)-a while initiating production of the anti-inflammatory cytokine IL-10. The critical importance of IL-10 in preventing chronic inflammation has long been appreciated, as evidenced by development of chronic colitis and early onset respectively, in mice or humans with genetic defects that cause inability to produce or respond to this cytokine.
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Intrinsic STING switches off pathogenetic programs of Th1 cells to inhibit colitis.
Cell Mol Gastroenterol Hepatol. 2023; (Online ahead of print)
5Yet, the notion that Th1 cells might be another source of IL-10 is relatively recent, in that research on IL-10 production has largely focused on antigen-presenting and T-reg cells.
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Predictive prenatal diagnosis for infantile-onset inflammatory bowel disease because of interleukin-10 signalling defects.
J Pediatr Gastroenterol Nutr. 2021; 72: 276-281
6Furthermore, mechanisms that govern Th1 cells to switch from a purely effector function to a dual effector/regulatory function had not been well-defined. Although the converting of IFN-γ+Th1 to IL-10+IFN-γ+Th1 cells was seen in response to pharmacologic STING activators, the physiologic importance of this pathway was seen in STING-deficient mice, which, in multiple models of colitis, exhibited exacerbated gut inflammation, accompanied by lack of IL-10 production by Th1 cells, which was not accompanied by altered development of other populations of T-cells.
- Jankovic D.
- Kullberg M.C.
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Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.
J Exp Med. 2007; 204: 273-283
STING-elicited production of Th1 cell IL-10 appears to proceed by previously established signaling cascades, involving type I interferon, STAT3 and Blimp-1, known to be activated by STING.
7In contrast, how STING is activated during colitis is not clear, but STING is known to sense DNA, and one can imagine a range of scenarios whereby host and/or microbial DNA is released as inflammation progresses, which might be a reasonably appropriate signal that curtailment of Th1 responsiveness is warranted. Interestingly, high doses of STING activators did not induce Th1 cells to produce IL-10 but rather led these cells to enter cell death pathways, thus suggesting that STING activation may not only nudge Th1 cells to shift from inflammation to resolution but can also give them an immediate order to cease and desist.
- Ishikawa H.
- Ma Z.
- Barber G.N.
STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.
Nature. 2009; 461: 788-792
The discovery of a new off switch for inflammation, particularly one on Th1 cells, begs the question of whether it can be harnessed to treat IBD. In support of this possibility, STING is indeed present on Th1 cells isolated from inflamed human biopsies, and furthermore, its pharmacologic activation induces Th1 cells to produce less pro-inflammatory cytokines (TNF-a and IL-6) and more IL-10. That expression of both STING and IL-10 are already both elevated in ulcerative colitis suggests these pathways are not defective in IBD per se but rather are already functioning to tamp down inflammation. Nonetheless, it is possible that further activation of STING, particularly if it could be achieved in a Th1 cell-specific manner, may have therapeutic value in this disorder.
- Dissecting the heterogeneity in T-cell mediated inflammation in IBD.Cells. 2020; 9: 110
- Cytokine networks and T-cell subsets in inflammatory bowel diseases.Inflamm Bowel Dis. 2016; 22: 1157-1167
- Mechanisms of immune suppression by myeloid-derived suppressor cells: the role of interleukin-10 as a key immunoregulatory cytokine.Open Biol. 2020; 10200111
- Intrinsic STING switches off pathogenetic programs of Th1 cells to inhibit colitis.Cell Mol Gastroenterol Hepatol. 2023; (Online ahead of print)
- Predictive prenatal diagnosis for infantile-onset inflammatory bowel disease because of interleukin-10 signalling defects.J Pediatr Gastroenterol Nutr. 2021; 72: 276-281
- Conventional T-bet(+)Foxp3(-) Th1 cells are the major source of host-protective regulatory IL-10 during intracellular protozoan infection.J Exp Med. 2007; 204: 273-283
- STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity.Nature. 2009; 461: 788-792
Published online: March 06, 2023
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Conflicts of interest The authors disclose no conflicts.
© 2023 The Authors. Published by Elsevier Inc.
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- Intrinsic STING Switches off Pathogenetic Programs of Th1 Cells to Inhibit ColitisCellular and Molecular Gastroenterology and HepatologyVol. 15Issue 5
- PreviewT helper 1 (Th1) effector cells are implicated in inflammatory bowel disease. The stimulator of interferon genes (STING), an intracellular DNA sensor, has been shown to regulate infection and various cancers. However, whether and how intrinsic STING signaling in Th1 cells regulates colitis is still unknown.