Mucosal T Cells Bearing TCRγδ Play a Protective Role in Intestinal Inflammation (original) (raw)
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American Journal of Physiology-Gastrointestinal and Liver Physiology, 1999
Inflammatory bowel disease (IBD) is a multifactorial immune disorder of uncertain etiology. The advent of several mouse models of mucosal inflammation that resemble IBD has provided insight into the mechanisms governing both normal and pathological mucosal immune function. In a widely used adoptive transfer model, the injection into immunodeficient mice of a subset of CD4+T lymphocytes, the CD4+CD45RBhighcells, leads to inflammation of the intestine. Pathogenesis is due in part to the secretion of proinflammatory cytokines. The induction of colitis can be prevented by cotransfer of another CD4+subpopulation, the CD4+CD45RBlowT cells. This population behaves analogously to the CD4+CD45RBhighpopulation in terms of the acquisition of activation markers and homing to the host intestine. However, their lymphokine profile when activated is different, and anti-inflammatory cytokines secreted and/or induced by CD4+CD45RBlowT cells prevent colitis. In this themes article, a description of th...
Regulation of mucosal immune responses — the missing link in IBD?
Inflammatory Bowel Disease, 1994
Although the etiology of inflammatory bowel disease (IBD) remains unknown, a major working hypothesis is that it represents a dysregulated immune response to common enteric bacterial antigens. Until recently there has been a relative dearth of experimental models to study this hypothesis. However, exciting developments in experimental models of colitis, including spontaneous, transgenic and knockout mice, now allow this and other hypotheses to be tested. The regulation of mucosal immune responses is not well understood in the normal animal, much less in those with chronic intestinal inflammation. Clearly the CD4 Th1 and Th2 pathways are important in the host response to microbial pathogens, and recent data indicate that the intestinal mucosa seems to be a site of preferential Th2 responses toward exogenous antigens. Deletion of certain cytokine genes involved in maintaining this Th1/Th2 balance (interleukin [IL]-2, IL-10) resulted in colitis, although deletion of others (IL-4, interferon-gamma) that are also involved did not. Whether these cytokine gene deletions cause a dysregulation of the mucosal immune response has yet to be shown. However, the importance of regulation can be demonstrated in a model in which a normal CD4 + T cell subset (CD45Rb high) is transferred into syngeneic severe combined immunodeficiency syndrome recipients. This results in a striking colitis over the ensuing weeks with chronic diarrhea and wasting of the animals. If the reciprocal CD4 + subset (CD45Rb low) is co-transferred or if whole CD4 + T cells are transferred no colitis ensues. Therefore, T cells capable of causing colitis are present in normal animals but are prevented from doing so by immunoregulatory mechanisms. The antigens that drive the colitis in several of these models (IL-2 knockout mouse, human leukocyte antigen B27/ß2M transgenic rat) appear to be those of the normal enteric bacterial flora because germ-free animals do not get the disease. Spontaneously colitic C3H/HeJBir mice also show prominent reactivity to enteric bacterial antigens. There are major differences among inbred mouse strains in susceptibility to colitis. The genes involved are not yet identified, but newly available technologies should allow that. In summary, these new models provide an experimental foundation to one of the major hypotheses on the cause of IBD, and will allow dissection of the genetic, environmental and immune components contributing to chronic colitis.
Editorial: Cytokines and Intestinal Mucosal Immunity
Frontiers in Immunology, 2021
Editorial on the Research Topic Cytokines and Intestinal Mucosal Immunity Since discovery of the prototypic cytokines, interleukin-1 (IL-1) and tumor necrosis factor-a (TNF), almost 50 years ago (1, 2), an explosion of information has followed regarding the biology of cytokines and their critical role(s) during health and disease. To date, 41 interleukins and more than 18 TNF superfamily (TNFSF) members have been described. Notably, in 1990, our group was one of the first to show that blockade of a single cytokine, i.e., IL-1, was effective in markedly reducing the severity of experimental colitis (3), laying the foundation to conceptualize that targeting of an individual cytokine could successfully impact the development and progression of a specific disease. The role of cytokines, in fact, has been particularly important in the gastrointestinal tract, both in maintaining homeostasis and during chronic inflammatory disorders, such as inflammatory bowel disease (IBD), wherein many cell types have the ability to both react to, and produce, cytokines in response to a variety of antigenic stimuli, dietary products, microbial components, and toxic agents. This wealth of new information has led to the approval of different anti-cytokine therapies, such as anti-TNF and anti-IL-12/23 monoclonal antibodies, for the treatment of both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD. In addition, novel small molecule inhibitors, such as those targeting the JAK/STAT pathway, and which possess broad anti-cytokine activity, are now available in the armamentarium of gastroenterologists to treat IBD. In this Research Topic, the role of canonical, and more novel, cytokines are discussed in the context of intestinal immunity and chronic gut inflammation. Three articles focus on the role(s) of TNFSF members (Li et al.; Valatas et al.; Giles et al.). Specifically, Li et al. and Valatas et al. report the importance of the TL1A (TNF-like ligand 1A, TNFSF15)/DR3 (death receptor 3,TNFRSF25) ligand-pair, for which increasing evidence suggests a critical role not only in the pathogenesis of IBD, but also in the development of gut fibrosis/fibrostenotic disease. These papers highlight TL1A/ DR3's pleiotropic functions in regulating the balance between T effector and T regulatory cells (Tregs), as well as innate lymphoid cells (ILCs), thereby serving as a vital rheostat during IBD. Notably, monoclonal antibodies against TL1A are currently in clinical trials for the treatment of CD and UC, and will shortly reveal the efficacy of anti-TL1A/DR3 strategies in IBD.
Molecular Medicine, 1997
Background: Although y6 T cells are a major component of the human intestinal mucosa, it is not clear what role they play in mucosal inimunity or if they are involved in the disease process of inflammatory bowel disease (IBD). Materials and Methods: Flow cytometry and reverse transcriptase-polymerase chain reaction (RT-PCR) assays were used to identify quantitative and qualitative changes in the repertoire of-y8T cells present in surgical and/or biopsy samples of normal and inflamed colon from individual patients with ulcerative colitis (UC) or Crohn's disease (CD). Cytokine production and the ability to adhere to and interact with colonic fibroblasts were used to compare the functional properties of yS T cells isolated from the normal and diseased colonic mucosa. Results: Increased numbers of yS T cells localized in areas of inflammation and tissue injury were found in the majority of patients, irrespective of the type of IBD present. This expansion was attributable to an increase in V61+ cells expressing a V5I-(D63)-J&1-encoded T cell receptor and was seen in patients with severe disease as well as those with newly diagnosed or less severe forms of IBD. Among T cells present in the inflamed mucosa of patients with CD, y8 T cells, particularly V81 + cells, were a major source of the proinflammatory cytokine interferon-y and could interact with colonic fibroblasts. Conclusions: Our results demonstrate that the chronic inflammatory immune response characteristic of IBD is associated with distinct changes in the number, distribution, composition, and function of mucosal 'yS T cells. Through the production of cytokines and physical interaction with other cells, y8 T cells can perform an immunoregulatory function and contribute to the pathophysiology of IBDs.
The TNF-family cytokine TL1A drives IL13-dependent small intestinal inflammation
Mucosal Immunology, 2011
The TNF family cytokine TL1A (TNFSF15) costimulates T cells through its receptor DR3 (TNFRSF25) and is required for autoimmune pathology driven by diverse T cell subsets. TL1A has been linked to human inflammatory bowel disease (IBD), but its pathogenic role is not known. We generated transgenic mice that constitutively express TL1A in T cells or dendritic cells. These mice spontaneously develop IL-13 dependent inflammatory small bowel pathology that strikingly resembles the intestinal response to nematode infections. These changes were dependent on the presence of a polyclonal TCR repertoire, suggesting that they are driven by components in the intestinal flora. FoxP3 + Treg were present in increased numbers despite the fact that TL1A suppresses the generation of inducible Treg. Finally, blocking TL1A-DR3 interactions abrogates TNBS-colitis, indicating that these interactions influence other causes of intestinal inflammation as well. These results establish a novel link between TL1A and IL-13 responses that results in small intestinal inflammation and establish that TL1A-DR3 interactions are necessary and sufficient for T cell-dependent IBD.