Signaling Lymphocyte Activation Molecule Regulates Development of Colitis in Mice (original) (raw)
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European Journal of Immunology, 2012
Dendritic cells (DCs) and monocyte-derived macrophages (M s) are key components of intestinal immunity. However, the lack of surface markers differentiating M s from DCs has hampered understanding of their respective functions. Here, we demonstrate that, using CD64 expression, M s can be distinguished from DCs in the intestine of both mice and humans. On that basis, we revisit the phenotype of intestinal DCs in the absence of contaminating M s and we delineate a developmental pathway in the healthy intestine that leads from newly extravasated Ly-6C hi monocytes to intestinal M s. We determine how inflammation impacts this pathway and show that T cell-mediated colitis is associated with massive recruitment of monocytes to the intestine and the mesenteric lymph node (MLN). There, these monocytes differentiate into inflammatory M s endowed with phagocytic activity and the ability to produce inducible nitric oxide synthase. In the MLNs, inflammatory M s are located in the T-cell zone and trigger the induction of proinflammatory T cells. Finally, T cell-mediated colitis develops irrespective of intestinal DC migration, an unexpected finding supporting an important role for MLN-resident inflammatory M s in the etiology of T cell-mediated colitis.
International Immunology, 2005
The b 2 integrin lymphocyte function-associated antigen-1 (LFA-1; CD11a/CD18) is important for lymphocyte trafficking and activation as well as recruitment to sites of tissue inflammation. The objective of this study was to assess the role of 'T-cell-associated' LFA-1 in the pathogenesis of chronic colitis in vivo. Transfer of CD4 1 CD25 ÿ T cells isolated from wild-type (wt) mice into immunodeficient recipients [recombinase-activating gene-1-deficient (RAG-1 ÿ/ÿ )] produced moderate to severe colitis, whereas RAG-1 ÿ/ÿ mice injected with CD11a-deficient (CD11a ÿ/ÿ ; LFA-1 ÿ/ÿ ) donor T cells displayed minimal macroscopic and histological evidence of colitis. Surface expression of L-selectin, a 4 , a 4 b 7 and chemokine receptor-7 were similar for wt and CD11a ÿ/ÿ donor T cells. Attenuated disease in the CD11a ÿ/ÿ ! RAG-1 ÿ/ÿ animals was associated with decreased numbers of CD4 1 T cells in the mesenteric lymph nodes (MLNs), spleen and intestinal lamina propria (LP). In addition, significant reductions in T h 1 cytokines were observed following ex vivo stimulation of mononuclear cells obtained from the MLNs and colonic LP. Interestingly, mononuclear cells obtained from the spleens of CD11a ÿ/ÿ ! RAG-1 ÿ/ÿ exhibited enhanced pro-inflammatory cytokine production compared with splenocytes obtained from wt ! RAG-1 ÿ/ÿ colitic mice. Taken together, our data suggest that T-cell-associated CD11a (LFA-1) expression plays a dual role in the initiation of chronic gut inflammation by facilitating naive T-cell priming/activation and expansion within MLNs and by augmenting pro-inflammatory cytokine production following secondary stimulation by antigenpresenting cells in the colonic interstitium.
Clinical and Experimental Immunology, 2005
Toll-like receptor 4 (TLR4), which recognizes lipopolysaccharides, plays an important role in the innate immune response. In this study, we investigated the role of TLR4 in the development of experimental colitis with regard to the biological actions of macrophage migration inhibitory factor (MIF) using TLR4 null ( -/-) mice. TLR4 -/mice were given 2% dextran sulphate sodium (DSS) in drinking water to induce colitis, which was clinically and histologically as severe as that seen in wild-type (WT) mice. The level of tumour necrosis factor (TNF)-a a a a in colon tissues was increased in WT mice but unchanged in TLR4 -/mice. The level of myeloperoxidase (MPO) activity in colon tissues was increased by DSS administration in both TLR4 -/and WT mice. The expression of MIF was up-regulated in the colons of TLR4 -/mice with acute DSS-induced colitis. An anti-MIF antibody significantly suppressed colitis and elevation of matrix metalloproteinase-13 in TLR4 -/mice. The current results obtained from TLR4 -/mice provide evidence that MIF plays a critical role in the development of acute DSS-induced colitis.
Journal of Experimental Medicine, 1999
In this study, we addressed the role of tumor necrosis factor (TNF)-α and lymphotoxin (LT)-α in the development of colitis and defined the cellular sources (T cells versus non-T cells) of TNF (TNF-α and LT-α) relevant to disease development. After adoptive transfer of TNF+/+ CD4+CD45RBhi splenocytes into TNF+/+ recombination activating gene (RAG)2−/− mice, the recipients develop massive inflammation of the large intestinal mucosa concurrent with massive weight loss. In contrast, clinical signs of disease are completely absent in TNF−/−RAG2−/− recipients of TNF−/− CD4+CD45RBhi T cells, although elevated numbers of interferon-γ–producing cells are present in the colonic mucosa. Surprisingly, upon transfer of TNF−/−CD4+CD45RBhi T cells into TNF+/+RAG2−/− recipients, colitis develops with kinetics similar to those upon transfer of TNF+/+CD4+CD45RBhi donor cells. In contrast, no clinical signs of colitis are observed in TNF−/−RAG2−/− recipients of TNF+/+CD4+CD45RBhi T cells. This protect...
Innate CD8αα+ lymphocytes enhance anti-CD40 antibody-mediated colitis in mice
Immunity, Inflammation and Disease, 2017
Introduction: Immune responses in the intestines require tight regulation to avoid uncontrolled inflammation. We previously described an innate lymphocyte population in the intestinal epithelium (referred to as innate CD8aa þ , or iCD8a cells) that can protect against gastrointestinal infections such as those mediated by Citrobacter rodentium. Methods: Here, we have evaluated the potential contribution of these cells to intestinal inflammation by analyzing inflammation development in mice with decreased numbers of iCD8a cells. We also determined the potential of iCD8a cells to secrete granzymes and their potential role during inflammatory processes. Results: We found that iCD8a cells play a pro-inflammatory role in the development of disease in a colitis model induced by anti-CD40 antibodies. We further found that the effects of iCD8a cells correlated with their capacity to secrete granzymes. We also observed that the pro-inflammatory properties of iCD8a cells were controlled by interactions of CD8aa homodimers on these cells with the thymus leukemia antigen expressed by intestinal epithelial cells. Conclusions: Our findings suggest that iCD8a cells modulate inflammatory responses in the intestinal epithelium, and that dysregulation of iCD8a cells effector functions may enhance disease. We propose that one of the mechanism by which iCD8a cells enhance inflammation is by the secretion of granzymes, which may promote recruitment of infiltrating cells into the epithelium.
American Journal of Physiology-Gastrointestinal and Liver Physiology, 2007
The induction and perpetuation of chronic colitis are thought to involve a complex set of adhesive interactions between T cells and endothelial cells located on the vasculature within secondary lymphoid tissue and the intestine. The objective of this study was to assess the roles of T cell-associated CD18, CD62L (L-selectin), ICAM-1, and P-selectin glycoprotein ligand-1 (PSGL-1) in the induction of chronic colitis in mice. CD4+CD25−T cells derived from either wild-type (WT), CD18-deficient [CD18 knockout (KO)], CD62L KO, ICAM-1 KO, or PSGL-1 KO mice were adoptively transferred into recombinase activating gene-1 (RAG-1)-deficient mice (RAG KO mice) to assess the potential of these T cells to induce chronic colitis. At 8–10 wk following T cell transfer, we observed moderate to severe colitis as assessed by increases in colon weight-to-length ratios and by blinded histopathological analysis. In contrast, we found that transfer of CD18 KO T cells into RAG KO recipients resulted in the s...
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...
T-cell regulation of neutrophil infiltrate at the early stages of a murine colitis model
Inflammatory Bowel Diseases, 2010
Background: T-cells are a main target for antiinflammatory drugs in inflammatory bowel disease. As the innate immune system is also implicated in the pathogenesis of these diseases, T-cell suppressors may not only inhibit T-cell-dependent production of proinflammatory mediators but also affect innate immune cell function. Specifically, these drugs may impair innate immune cell recruitment and activation through inhibition of T-cells or act independent of T-cell modulation. We explored the extent of immune modulation by the T-cell inhibitor tacrolimus in a murine colitis model.