Type 1 and 2 T Helper Cell-mediated Colitis
Purpose of Review: Abrogation of mucosal T cell homeostasis by exaggerated not only T helper 1, but also T helper 2 cells is a major problem that leads to intestinal inflammation. In this regard, it is important to understand these different aspects of mucosal inflammation.
Recent Findings: Both T helper 1 and 2 cells play central roles in the induction of mucosal immune responses including secretory IgA antibody production, which would be the most beneficial aspect for the host defense mechanism. T helper 1- and 2-type responses, however, exhibit other roles in the abrogation of intestinal homeostasis. Although it has been shown that T helper 1-type immune responses are key players in the induction of intestinal inflammation in mice colitis models and also in inflammatory bowel diseases in humans, studies in murine colitis models clearly show that T helper 2-type responses are also involved in the pathophysiology of the intestinal inflammation. Both regulatory type T cells and T helper 17 cells are involved to down- or upregulate aberrant T helper 1 and 2 cell responses.
Summary: Understanding the cellular and molecular mechanisms of crosstalk among T helper 1, 2, 17 and T regulatory 1 cells is central for the prevention or treatment of inflammatory bowel diseases.
That a highly integrated and finely regulated mucosal immune system exists alongside and separate from the peripheral system might at first seem redundant and puzzling. Why should such a separate and sophisticated system be necessary when the peripheral immune system already seems to ensure immunity for the host? There can be no doubt about the sophistication and elegance of the mucosal immune system. It presents a well-tuned, two-part defense - one more structured and localized, one more diffuse. In the first, foreign antigens are encountered and selectively taken up into highly structured sites for the initiation of immune responses. In the second, diffuse distribution of effector cells such as B and T lymphocytes, differentiated plasma cells, macrophages, and other antigen-presenting cells as well as eosinophils, basophils and, especially, mast cells come into play. Together, the two either produce mucosal and serum antibody responses and T cell-mediated immunity, on the one hand, or systemic anergy (commonly termed oral tolerance), on the other hand. Such a separate and sophisticated immune system may well have evolved as a major defense mechanism against mucosally encountered infectious agents as well as to attenuate mucosal inflammation through tolerance induction.
Human inflammatory bowel diseases (IBDs) are characterized by episodes of abdominal pain, diarrhea, bloody stools, weight loss and intestinal inflammation. It is generally agreed that human IBDs are multifactorial with immunologic, environmental and genetic contributions making systematic studies difficult. The recently developed murine models for human IBD serve as excellent examples of current attempts to determine how aberrant immune responses lead to mucosal inflammation (Fig. 1). Further, as mechanisms whereby T cells and cytokines are better defined in the development of IBD, this may provide an opportunity to develop vaccine strategies for induction of oral tolerance to either diminish or prevent colonic inflammation. To obviate these difficulties, mice have been treated with chemical haptens or modified immunologically to induce colonic inflammation. In these models, some mouse strains exhibit greater susceptibility, suggesting significant genetic control in the development of IBD. Thus far, large numbers of experimental murine IBD models have been reported, including spontaneous colitis, colitis induced by exogenous agents, transgenic or knockout mice and colitis induced by lack of regulatory type T (Treg) cells. In this review, we discuss murine experimental colitis models which are mainly mediated by T helper (Th) 1- and 2-type CD4 T cells.
(Enlarge Image)
Colitis induction by aberrant T helper (Th) 1 and 2 immune responses. Several murine models of inflammatory bowel disease suggest that CD4R Th1-type responses and interferon-g are major factors in the development of colonic inflammation. In addition, studies now suggest that aberrant CD4R Th2-type cells are associated with colonic patch hypertrophy and colitis in murine model. Balanced Th1- and 2-type response is essential for the maintenance of intestinal homeostasis. Ag, antigen; IL, interleukin; KO, knockout, OVA, ovalbumin; TCR, T cell receptor; Tg, transgenic; TGF, transforming growth factor; TNBS, 2,4,6-trinitrobenzene sulfonic acid; Treg/r, T regulatory.
Purpose of Review: Abrogation of mucosal T cell homeostasis by exaggerated not only T helper 1, but also T helper 2 cells is a major problem that leads to intestinal inflammation. In this regard, it is important to understand these different aspects of mucosal inflammation.
Recent Findings: Both T helper 1 and 2 cells play central roles in the induction of mucosal immune responses including secretory IgA antibody production, which would be the most beneficial aspect for the host defense mechanism. T helper 1- and 2-type responses, however, exhibit other roles in the abrogation of intestinal homeostasis. Although it has been shown that T helper 1-type immune responses are key players in the induction of intestinal inflammation in mice colitis models and also in inflammatory bowel diseases in humans, studies in murine colitis models clearly show that T helper 2-type responses are also involved in the pathophysiology of the intestinal inflammation. Both regulatory type T cells and T helper 17 cells are involved to down- or upregulate aberrant T helper 1 and 2 cell responses.
Summary: Understanding the cellular and molecular mechanisms of crosstalk among T helper 1, 2, 17 and T regulatory 1 cells is central for the prevention or treatment of inflammatory bowel diseases.
That a highly integrated and finely regulated mucosal immune system exists alongside and separate from the peripheral system might at first seem redundant and puzzling. Why should such a separate and sophisticated system be necessary when the peripheral immune system already seems to ensure immunity for the host? There can be no doubt about the sophistication and elegance of the mucosal immune system. It presents a well-tuned, two-part defense - one more structured and localized, one more diffuse. In the first, foreign antigens are encountered and selectively taken up into highly structured sites for the initiation of immune responses. In the second, diffuse distribution of effector cells such as B and T lymphocytes, differentiated plasma cells, macrophages, and other antigen-presenting cells as well as eosinophils, basophils and, especially, mast cells come into play. Together, the two either produce mucosal and serum antibody responses and T cell-mediated immunity, on the one hand, or systemic anergy (commonly termed oral tolerance), on the other hand. Such a separate and sophisticated immune system may well have evolved as a major defense mechanism against mucosally encountered infectious agents as well as to attenuate mucosal inflammation through tolerance induction.
Human inflammatory bowel diseases (IBDs) are characterized by episodes of abdominal pain, diarrhea, bloody stools, weight loss and intestinal inflammation. It is generally agreed that human IBDs are multifactorial with immunologic, environmental and genetic contributions making systematic studies difficult. The recently developed murine models for human IBD serve as excellent examples of current attempts to determine how aberrant immune responses lead to mucosal inflammation (Fig. 1). Further, as mechanisms whereby T cells and cytokines are better defined in the development of IBD, this may provide an opportunity to develop vaccine strategies for induction of oral tolerance to either diminish or prevent colonic inflammation. To obviate these difficulties, mice have been treated with chemical haptens or modified immunologically to induce colonic inflammation. In these models, some mouse strains exhibit greater susceptibility, suggesting significant genetic control in the development of IBD. Thus far, large numbers of experimental murine IBD models have been reported, including spontaneous colitis, colitis induced by exogenous agents, transgenic or knockout mice and colitis induced by lack of regulatory type T (Treg) cells. In this review, we discuss murine experimental colitis models which are mainly mediated by T helper (Th) 1- and 2-type CD4 T cells.
(Enlarge Image)
Colitis induction by aberrant T helper (Th) 1 and 2 immune responses. Several murine models of inflammatory bowel disease suggest that CD4R Th1-type responses and interferon-g are major factors in the development of colonic inflammation. In addition, studies now suggest that aberrant CD4R Th2-type cells are associated with colonic patch hypertrophy and colitis in murine model. Balanced Th1- and 2-type response is essential for the maintenance of intestinal homeostasis. Ag, antigen; IL, interleukin; KO, knockout, OVA, ovalbumin; TCR, T cell receptor; Tg, transgenic; TGF, transforming growth factor; TNBS, 2,4,6-trinitrobenzene sulfonic acid; Treg/r, T regulatory.