T cell-mediated immunoregulation in the gastrointestinal
The potential relevance of systemic and gastrointestinal immune activation in the pathophysiology and symptom generation in the irritable bowel syndrome (IBS) is supported by a number of observations. Infectious gastroenteritis is the strongest risk factor for the development of IBS and increased rates of IBS-like symptoms have been detected in patients with inflammatory bowel disease in remission or in celiac disease patients on a gluten free diet. The number of T cells and mast cells in the small and large intestine of patients with IBS is increased in a large proportion of patients with IBS over healthy controls. Mediators released by immune cells and likely from other non-immune competent cells impact on the function of enteric and sensory afferent nerves as well as on epithelial tight junctions controlling mucosal barrier of recipient animals, isolated human gut tissues or cell culture systems. Antibodies against microbiota antigens (bacterial flagellin), and increased levels of cytokines have been detected systemically in the peripheral blood advocating the existence of abnormal host-microbial interactions and systemic immune responses. Nonetheless, there is wide overlap of data obtained in healthy controls; in addition, the subsets of patients showing immune activation have yet to be clearly identified. Gender, age, geographic differences, genetic predisposition, diet and differences in the intestinal microbiota likely play a role and further research has to be done to clarify their relevance as potential mechanisms in the described immune system dysregulation. Immune activation has stimulated interest for the potential identification of biomarkers useful for clinical and research purposes and the development of novel therapeutic approaches.
Mechanisms of intestinal immune regulation
Several factors have been identified to be critical for Treg function, including IL-10, IL-2, TGF-β and cytotoxic T lymphocyte antigen-4 (CTLA-4).While mice deficient for the latter exhibit multiorgan autoimmune disease, which is rapidly fatal in the case of TGF-β or CTLA-4 knockout (KO), IL-10-deficient mice reach adulthood without signs of severe disease.However, in the presence of bacteria such as Helicobacter hepaticus, which is common in animal facilities, the mice develop spontaneous intestinal inflammation, indicating a major role for IL-10 in gut homeostasis.Indeed, Foxp3+ Treg isolated from spleen or MLN produce very little IL-10, whereas it is produced by a significant proportion of Foxp3+ cells isolated from the colonic lamina propria, and also by some Foxp3− cells in the intestine.Interestingly, IL-10 is not required for the prevention of colitis induced by naïve T-cell transfer into immunodeficient recipients.However, it is necessary to abrogate established intestinal inflammation, as CD25+ Treg cannot cure T-cell transfer-induced colitis if the IL-10 signalling pathway is blocked, and Treg-produced IL-10 plays a significant role in protection.Similarly, IL-10 production is essential for Treg-mediated prevention of colitis caused by antigen-experienced IL-10 KO cells isolated from the MLN. These data are consistent with a specific role for IL-10 in controlling intestinal inflammation, while being dispensable for the control of immune responses initiated systemically.
The targets of IL-10 in the intestine have not been fully characterized yet. IL-10 is an immunoregulatory cytokine which can act on T cells and other components of the immune system.IL-10 is required for Treg to prevent colitis in an innate model of intestinal inflammation, suggesting that IL-10 not only controls pathogenic T cells, but can act on other immune cells in the intestine.Complementing these data, conditional knockouts lacking signal transducer and activator of transcription-3 (STAT3), an essential mediator of IL-10 signalling, specifically in macrophages and neutrophils develop colitis. The relative importance of IL-10 in controlling myeloid and T-cell responses during intestinal inflammation in intact mice remains to be ascertained.
The fact that Treg-derived IL-10 is essential for the control of certain pathologies, such as colitis, and dispensable to regulate other disorders is intriguing, but not at all unique. Other Treg-associated molecules, such as CTLA-4 and TGF-β, show similar results. For example, CTLA-4-deficient Treg can still prevent disease in vivo, but not if the effector cells also lack CTLA-4.Similarly, TGF-β1 production by Treg appears to be essential in one report and dispensable in another one.These discrepancies are compatible with a model where Foxp3+ Treg can regulate via several independent mechanisms that have partially overlapping functions. The particular mechanism required in each case will depend on the nature of the inflammatory stimulus, the inflammatory cells that have to be controlled and the location in which the response is taking place.
While it remains to de determined to what extent Treg-derived IL-10 is also necessary to control inflammation in other organs apart from the gut, it is not surprising that systemic and tissue-specific inflammation are controlled by partly different mechanisms. Indeed, different inflammatory pathways have been shown to mediate systemic wasting disease and colitis in an experimental model. As a result of the special challenges the intestinal immune system has to confront, it is not impossible that its reactivity is controlled in different ways to the central immune system. Similarly, other tissues are also likely to have different regulatory requirements to the central lymphoid organs.
T cell-mediated immunoregulation in the gastrointestinal tract.
In the intestinal tract, only a single layer of epithelial cells separates innate and adaptive immune effector cells from a vast amount of antigens. Here, the immune system faces a considerable challenge in tolerating commensal flora and dietary antigens while preventing the dissemination of potential pathogens.
Failure to tightly control immune reactions may result in detrimental inflammation. In this respect, ‘conventional’ regulatory CD4(+) T cells, including naturally occurring and adaptive CD4(+) CD25(+) Foxp3(+) T cells, Th3 and Tr1 cells, have recently been the focus of considerable attention. However, regulatory mechanisms in the intestinal mucosa are highly complex, including adaptations of nonhaematopoietic cells and innate immune cells as well as the presence of unconventional T cells with regulatory properties such as resident TCRgammadelta or TCRalphabeta CD8(+) intraepithelial lymphocytes. This review aims to summarize the currently available knowledge on conventional and unconventional regulatory T cell subsets (Tregs), with special emphasis on clinical data and the potential role or malfunctioning of Tregs in four major human gastrointestinal diseases, i.e. inflammatory bowel diseases, coeliac disease, food allergy and colorectal cancer. We conclude that the clinical data confirms some but not all of the findings derived from experimental animal models.
Suppression of chronic intestinal inflammation by different subtypes of T cells has been described in recent years. In particular, naturally arising CD4(+)CD25(+) regulatory T cells and IL-10-producing regulatory T cell type 1 CD4(+) T lymphocytes have been implicated in the regulation of intestinal inflammation. Here we focus on the ability of CD4(+)CD25(+) regulatory T cells to suppress innate and T-cell responses and discuss implications for immunoregulation in human inflammatory bowel disease.
Besides the modulation of lymphoproliferation, a role for CD4(+)CD25(+) T cells in down-modulation of innate immune responses is emerging and the immunoregulatory activities of regulatory T cells in vivo may be mediated via effects on dendritic cells. Considering the extraordinary regenerative potential of the intestinal mucosa, the ability to impede pathogenic T-cell responses by active regulation might be of particular therapeutic benefit for the treatment of chronic intestinal inflammatory diseases such as Crohn’s disease and ulcerative colitis.
The gastrointestinal (GI) tract is the main interface where the body encounters exogenous antigens. It is crucial that the local response here is tightly regulated to avoid an immune reaction against dietary antigens and commensal flora while still mounting an efficient defense against pathogens. Faults in establishing intestinal tolerance can lead to disease, inducing local and often also systemic inflammation. Studies in human as well as in animal models suggest a role for regulatory T cells (Tregs) in maintaining intestinal homeostasis. Transfer of Tregs can not only prevent the development of colitis in animal models but also cure established disease, acting both systemically and at the site of inflammation. In this review, we discuss the major regulatory pathways, including transforming growth factor-beta (TGF-beta), interleukin-10 (IL-10), and cytotoxic T-lymphocyte antigen-4 (CTLA-4), and their role in Treg-mediated control of systemic and mucosal responses. In addition, we give an overview of the known mechanisms of lymphocyte migration to the intestine and discuss how CD103 expression can influence the balance between regulatory and effector T cells. Further understanding of the factors that control the activity of Tregs in different immune compartments may facilitate the design of strategies to target regulation in a tissue-specific way.
Many different pathways contribute to the maintenance of tolerance to harmless antigens in the intestine. When these important pathways are compromised, chronic intestinal inflammation can develop. In particular, naturally occurring CD4+CD25+ regulatory T cells have been shown to play an important role in the prevention and cure of colitis in animal models of intestinal inflammation. These regulatory T cell responses may be influenced by the local environment in the intestine. For example, functionally specialised populations of dendritic cells exist in the intestine which may favour regulatory type responses. Understanding how these pathways intersect may lead to the development of more specific therapies for the treatment of inflammatory bowel disease.
Special regulatory T-cell review: regulatory T cells and the intestinal tract – patrolling the frontier
Evidence for active T-cell mediated regulatory mechanisms was found in the 1970s with the discovery of ‘suppressor T cells’.However, the cellular and molecular basis of this phenomenon was not clearly established and studies in this area were largely abandoned in the 1980s.
In spite of this, a few groups continued to investigate dominant T-cell mediated immunoregulatory pathways. In these models, induction of lymphopenia through irradiation and/or neonatal thymectomy led not only to impaired immune responses, but paradoxically also to autoimmunity. Importantly, transfer of normal lymphocytes could prevent disease.Development of monoclonal antibodies allowed further characterization of the cell populations that could mediate suppression with evidence in T cell transfer experiments that both pathology and protection from disease were mediated by T cells.Importantly, naïve CD4+ T cells isolated from unmanipulated healthy animals also induced disease when transferred into immunodeficient recipients, showing that pathogenic cells are present in the normal T-cell repertoire.Self-reactive T cells were further identified in healthy humans.Despite these findings, autoimmune disease is relatively rare, indicating that regulatory mechanisms normally control this pathogenic activity.In complementary experiments, T cells with the ability to inhibit pathogenic responses were isolated from unmanipulated rodents.
Further fractionation of the CD4+ T-cell subset showed that immune suppressive activity was enriched within the Lyt-1+ subset in mice and in the antigen-experienced CD45RClow fraction in rats.Encounter with the antigen in the periphery, however, did not seem to be essential for acquiring regulatory activity, as in vivo tolerance could also be achieved by the transfer of CD4 single positive thymocytes.In vivo subset analysis by Sakaguchi et al.14 showed that the regulatory activity was enriched within the CD25+ population; this population was then found in humans and shown to suppress in vitro T-cell responses.15–17 While CD25 remains the most widely used regulatory T cell (Treg) surface marker, it is neither Treg exclusive nor expressed by all Treg. The CD25+ T cell population still includes activated T cells with pathogenic rather than regulatory potential. Furthermore, the CD45RBlow CD25− population still possesses some regulatory activity. A more definitive Treg marker was needed.
The answer came from the studies of a naturally occurring mouse mutation called scurfy. Scurfy mice have a mutation in the Foxp3 gene on the X chromosome.Affected males suffer from a severe autoimmune syndrome, similar to the human IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked) syndrome, which is also caused by mutations in FOXP3 Interestingly, the mouse disease is mediated by T cells and has some similar features to the disease induced by transfer of Treg-depleted subsets. In 2003, three independent groups found that the transcription factor Foxp3 is highly expressed in the CD4+ CD25+ T cell subset.Moreover, enforced Foxp3 expression in naïve T cells endowed them with regulatory activity in vitro and in vivo. Further analyses have confirmed Foxp3 as a key gene for Treg generation and maintenance, and it is now the most widely used marker for Treg, despite some reports indicating that it can be transiently expressed by non-Treg in humans. The identification of the link between Foxp3 and Treg has been instrumental for many recent studies on regulation, allowing identification of Treg by flow cytometry and immunohistochemistry, and not solely on the basis of their activity.
Treg and intestinal responses
While IPEX can affect many organs, one of the most common features is intestinal inflammation. The gastrointestinal tract represents the main surface by which the organism encounters exogenous antigens. In addition to its diverse dietary antigens, it is home to a vast number of commensal bacteria. These foreign antigens however do not induce inflammation under normal conditions, pointing to a system to downregulate inappropriate immune responses in the intestine. Still, lack of intestinal inflammation does not mean absence of immune responses, as shown by the fact that immunodeficient individuals often get opportunistic infections by members of the normal commensal flora. On the other hand, a dysregulated, over-exuberant response to the intestinal flora is believed to play a role in chronic intestinal pathologies such as inflammatory bowel disease. Thus, the immune response in the intestine has to be finely tuned to avoid infection while remaining tolerant to food antigens and resident bacteria.
Foxp3+ Treg are known to play an important role in intestinal homeostasis. Besides the evidence from IPEX patients, transfer of Treg inhibits experimental colitis induced when naïve T cells are injected into immunodeficient mice and react to the intestinal flora. Strikingly, Treg can also cure established colitis and this is associated with their proliferation in the intestine. Although most studies concerning Treg and intestinal homeostasis have focused on thymically imprinted natural Treg, there is also evidence that the intestine with its associated lymphoid tissue is a site for induction of Foxp3+ Treg from naïve precursors. Dendritic cells (DC) are essential in antigen presentation, and they seem to play an important role in Treg generation. Functionally specialized intestinal DC that express the integrin CD103 have been linked to Treg development. CD103+ DC are enriched in the colon and in the mesenteric lymph nodes (MLN), and CD103+, but not CD103−, MLN DC can induce gut-homing receptors on naïve T cells. Importantly, CD103+ DC can also induce Foxp3+ Treg in an antigen-specific manner, through a mechanism depending on transforming growth factor-β (TGF-β) and retinoic acid.38,39 This could represent a mechanism to generate specific regulation to local, non-thymically expressed antigens. It does not however necessarily mean that only peripherally induced Foxp3+ cells can control intestinal inflammation. Indeed, CD4+ CD25+ Treg isolated from the spleen or thymus can prevent intestinal inflammation in T-cell transfer colitis.40 Clearly much remains to be learnt about the roles of thymically arisen and peripherally induced Treg in tolerance towards foreign antigens.
- Saurer L, et al. T cell-mediated immunoregulation in the gastrointestinal tract. Allergy. 2009 Apr;64(4):505-19.
- Uhlig HH, et al. The role of mucosal T lymphocytes in regulating intestinal inflammation. Springer Semin Immunopathol. 2005 Sep;27(2):167-80.
- Izcue A, et al. Regulatory T cells suppress systemic and mucosal immune activation to control intestinal inflammation. Immunol Rev. 2006 Aug;212:256-71.
- Coombes JL, et al. Control of intestinal homeostasis by regulatory T cells and dendritic cells. Semin Immunol. 2007 Apr;19(2):116-26.
- Ana Izcue, Fiona Powrie. Special regulatory T-cell review: regulatory T cells and the intestinal tract – patrolling the frontier Immunology. 2008 January; 123(1): 6–10.
- Macdonald TT, Monteleone G. Immunity, inflammation, and allergy in the gut. Science. 2005;307:1920–5
- Aranda R, Sydora BC, McAllister PL, Binder SW, Yang HY, Targan SR, Kronenberg M. Analysis of intestinal lymphocytes in mouse colitis mediated by transfer of CD4+, CD45RBhigh T cells to SCID recipients. J Immunol. 1997;158:3464–73.
- Powrie F, Mauze S, Coffman RL. CD4+ T-cells in the regulation of inflammatory responses in the intestine. Res Immunol. 1997;148:576–81.
- Sartor RB. The influence of normal microbial flora on the development of chronic mucosal inflammation. Res Immunol. 1997;148:567–76
- Uhlig HH, Coombes J, Mottet C, et al. Characterization of Foxp3+ CD4+ CD25+ and IL-10-secreting CD4+ CD25+ T cells during cure of colitis. J Immunol. 2006;177:5852–60
- Kretschmer K, Apostolou I, Hawiger D, Khazaie K, Nussenzweig MC, von Boehmer H. Inducing and expanding regulatory T cell populations by foreign antigen. Nat Immunol. 2005;6:1219–27.
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