scholarly journals Enhanced Susceptibility of Galectin-1 Deficient Mice to Experimental Colitis

2021 ◽  
Vol 12 ◽  
Author(s):  
Raquel Fernandez-Perez ◽  
Mercedes Lopez-Santalla ◽  
Rebeca Sánchez-Domínguez ◽  
Omaira Alberquilla ◽  
Irene Gutiérrez-Cañas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Cell Trafficking ◽  
Wild Type ◽  
Cell Reactivity ◽  
Deficient Mice

Galectin-1 is a β-galactoside-binding lectin, ubiquitously expressed in stromal, epithelial, and different subsets of immune cells. Galectin-1 is the prototype member of the galectin family which shares specificity with β-galactoside containing proteins and lipids. Immunomodulatory functions have been ascribed to endogenous galectin-1 due to its induction of T cell apoptosis, inhibitory effects of neutrophils and T cell trafficking. Several studies have demonstrated that administration of recombinant galectin-1 suppressed experimental colitis by modulating adaptive immune responses altering the fate and phenotype of T cells. However, the role of endogenous galectin-1 in intestinal inflammation is poorly defined. In the present study, the well-characterized acute dextran sulfate sodium (DSS)-induced model of ulcerative colitis was used to study the function of endogenous galectin-1 during the development of intestinal inflammation. We found that galectin-1 deficient mice (Lgals1−/− mice) displayed a more severe intestinal inflammation, characterized by significantly elevated clinical scores, than their wild type counterparts. The mechanisms underlying the enhanced inflammatory response in colitic Lgals1−/− mice involved an altered Th17/Th1 profile of effector CD4+ T cells. Furthermore, increased frequencies of Foxp3+CD4+ regulatory T cells in colon lamina propria in Lgals1−/− mice were found. Strikingly, the exacerbated intestinal inflammatory response observed in Lgals1−/− mice was alleviated by adoptive transfer of wild type Foxp3+CD4+ regulatory T cells at induction of colitis. Altogether, these data highlight the importance of endogenous galectin-1 as a novel determinant in regulating T cell reactivity during the development of intestinal inflammation.

Abstract 5448: Regulatory T Cells Control Post-Ischemic Neovascularization

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Yasmine Zouggari ◽  
Hafid Ait-Oufella ◽  
Ludovic Waeckel ◽  
José Vilar ◽  
Céline Loinard ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Inflammatory Response ◽  
Treg Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Critical Role ◽  
Vessel Growth ◽  
Deficient Mice

CD4+ and CD8+ T lymphocytes are key regulators of post-ischemic neovascularization. T cell activation is promoted by two major costimulatory signalings: the CD28/B7 and the CD40ligand-CD40 pathways. Interestingly, CD28 interactions with the structurally related ligands B7–1 and B7–2 are also required for the generation and homeostasis of CD4+CD25+ regulatory T cells (Treg), which play a critical role in the suppression of immune responses and the control of T-cell homeostasis. We hypothesized that Treg cell activation may modulate the immuno-inflammatory response to ischemic injury, leading to alteration of post-ischemic vessel growth. Ischemia was induced by right femoral artery ligation in CD28-, B7–1/2- or CD40-deficient mice (n=10 per group). CD40 deficiency did not affect Treg levels and led to significant reduction in post-ischemic inflammatory response and vessel growth. In contrast, at day 21 after ischemia, angiographic score, foot perfusion, and capillary density were increased by 2.0-, 1.2-, and 1.8-fold respectively in CD28-deficient mice, which show profound reduction in Treg, compared to controls. Similarly, disruption of B7–1/2 signaling and subsequent Treg deletion significantly enhanced post-ischemic neovascularization. These effects were associated with enhanced accumulation of CD3-positive T cells and Mac-3 positive macrophages in the ischemic leg of CD28−/− or B7−/− mice compared with controls. Proinflammatory cytokines, IL-1β, TNF-α and IL-6, were also upregulated and antiinflammatory mediators, IL-10 and TGF-β1 downregulated in the ischemic legs of CD28−/− or B7−/− mice. Finally, treatment of CD28−/− mice with the nonmitogenic anti-CD3 monoclonal antibody enhanced expression of the regulatory T-cell marker Foxp3 in blood and ischemic tissue of CD28−/− mice, led to reduction in post-ischemic inflammatory response and neovascularization in CD28-deficient mice. In conclusion, endogenous Treg cell response controls post-ischemic neovascularization.

scholarly journals A role for CD9 molecules in T cell activation.

1996 ◽  
Vol 184 (2) ◽  
pp. 753-758 ◽  
Author(s):  
X G Tai ◽  
Y Yashiro ◽  
R Abe ◽  
K Toyooka ◽  
C R Wood ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Activation ◽  
Cell Activation ◽  
Expression Cloning ◽  
Wild Type ◽  
Almost All ◽  
Antigen Presenting ◽  
Deficient Mice

Costimulation mediated by the CD28 molecule plays an important role in optimal activation of T cells. However, CD28-deficient mice can mount effective T cell-dependent immune responses, suggesting the existence of other costimulatory systems. In a search for other costimulatory molecules on T cells, we have developed a monoclonal antibody (mAb) that can costimulate T cells in the absence of antigen-presenting cells (APC). The molecule recognized by this mAb, 9D3, was found to be expressed on almost all mature T cells and to be a protein of approximately 24 kD molecular mass. By expression cloning, this molecule was identified as CD9, 9D3 (anti-CD9) synergized with suboptimal doses of anti-CD3 mAb in inducing proliferation by virgin T cells. Costimulation was induced by independent ligation of CD3 and CD9, suggesting that colocalization of these two molecules is not required for T cell activation. The costimulation by anti-CD9 was as potent as that by anti-CD28. Moreover, anti-CD9 costimulated in a CD28-independent way because anti-CD9 equally costimulated T cells from the CD28-deficient as well as wild-type mice. Thus, these results indicate that CD9 serves as a molecule on T cells that can deliver a potent CD28-independent costimulatory signal.

scholarly journals Protease-Activated Receptor 2 Has Pivotal Roles in Cellular Mechanisms Involved in Experimental Periodontitis

2009 ◽  
Vol 78 (2) ◽  
pp. 629-638 ◽  
Author(s):  
David M. Wong ◽  
Vivian Tam ◽  
Roselind Lam ◽  
Katrina A. Walsh ◽  
Liliana Tatarczuch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Mast Cells ◽  
Bone Resorption ◽  
Inflammatory Response ◽  
T Cell Activation ◽  
Interleukin 2 ◽  
Wild Type ◽  
Periodontal Tissues ◽  
Protease Activated Receptor 2

ABSTRACT The tissue destruction seen in chronic periodontitis is commonly accepted to involve extensive upregulation of the host inflammatory response. Protease-activated receptor 2 (PAR-2)-null mice infected with Porphyromonas gingivalis did not display periodontal bone resorption in contrast to wild-type-infected and PAR-1-null-infected mice. Histological examination of tissues confirmed the lowered bone resorption in PAR-2-null mice and identified a substantial decrease in mast cells infiltrating the periodontal tissues of these mice. T cells from P. gingivalis-infected or immunized PAR-2-null mice proliferated less in response to antigen than those from wild-type animals. CD90 (Thy1.2) expression on CD4+ and CD8+ T-cell-receptor β (TCRβ) T cells was significantly (P < 0.001) decreased in antigen-immunized PAR-2-null mice compared to sham-immunized PAR-2-null mice; this was not observed in wild-type controls. T cells from infected or antigen-immunized PAR-2-null mice had a significantly different Th1/inflammatory cytokine profile from wild-type cells: in particular, gamma interferon, interleukins (interleukin-2, -3, and -17), granulocyte-macrophage colony-stimulating factor, and tumor necrosis factor alpha demonstrated lower expression than wild-type controls. The absence of PAR-2 therefore appears to substantially decrease T-cell activation and the Th1/inflammatory response. Regulation of such proinflammatory mechanisms in T cells and mast cells by PAR-2 suggests a pivotal role in the pathogenesis of the disease.

Role of α/β and γ/δ T cells in renal ischemia-reperfusion injury

2007 ◽  
Vol 293 (3) ◽  
pp. F741-F747 ◽  
Author(s):  
Kathrin Hochegger ◽  
Tobias Schätz ◽  
Philipp Eller ◽  
Andrea Tagwerker ◽  
Dorothea Heininger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Wild Type ◽  
Renal Ischemia Reperfusion Injury ◽  
Deficient Mice

T cells have been implicated in the pathogenesis of renal ischemia-reperfusion injury (IRI). To date existing data about the role of the T cell receptor (Tcr) are contradictory. We hypothesize that the Tcr plays a prominent role in the late phase of renal IRI. Therefore, renal IRI was induced in α/β, γ/δ T cell-deficient and wild-type mice by clamping renal pedicles for 30 min and reperfusing for 24, 48, 72, and 120 h. Serum creatinine increased equally in all three groups 24 h after ischemia but significantly improved in Tcr-deficient animals compared with wild-type controls after 72 h. A significant reduction in renal tubular injury and infiltration of CD4+ T-cells in both Tcr-deficient mice compared with wild-type controls was detected. Infiltration of α/β T cells into the kidney was reduced in γ/δ T cell-deficient mice until 72 h after ischemia. In contrast, γ/δ T cell infiltration was equal in wild-type and α/β T cell-deficient mice, suggesting an interaction between α/β and γ/δ T cells. Data from γ/δ T cell-deficient mice were confirmed by in vivo depletion of γ/δ T cells in C57BL/6 mice. Whereas α/β T cell-deficient mice were still protected after 120 h, γ/δ T cell-deficient mice showed a “delayed wild-type phenotype” with a dramatic increase in kidney-infiltrating α/β, Tcr-expressing CD4+ T-cells. This report provides further evidence that α/β T cells are major effector cells in renal IRI, whereas γ/δ T cells play a role as mediator cells in the first 72 h of renal IRI.

scholarly journals Cytomegalovirus-specific T-cell reactivity in biliary atresia at the time of diagnosis is associated with deficits in regulatory T cells

Hepatology ◽  
2012 ◽  
Vol 55 (4) ◽  
pp. 1130-1138 ◽  
Author(s):  
Stephen M. Brindley ◽  
Allison M. Lanham ◽  
Frederick M. Karrer ◽  
Rebecca M. Tucker ◽  
Andrew P. Fontenot ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Biliary Atresia ◽  
Cell Reactivity ◽  
T Cell Reactivity

scholarly journals IL10-Deficiency in CD4+ T Cells Exacerbates the IFNγ and IL17 Response During Bacteria Induced Colitis

2015 ◽  
Vol 36 (4) ◽  
pp. 1259-1273 ◽  
Author(s):  
Virginia Seiffart ◽  
Julia Zoeller ◽  
Robert Klopfleisch ◽  
Munisch Wadwa ◽  
Wiebke Hansen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
T Cell Activation ◽  
Cd4 T Cells ◽  
Cell Activation ◽  
Intestinal Inflammation ◽  
Cd4 T Cell ◽  
Intestinal Homeostasis ◽  
Crypt Hyperplasia

Background/Aims: IL10 is a key inhibitor of effector T cell activation and a mediator of intestinal homeostasis. In addition, IL10 has emerged as a key immunoregulator during infection with various pathogens, ameliorating the excessive T-cell responses that are responsible for much of the immunopathology associated with the infection. Because IL10 plays an important role in both intestinal homeostasis and infection, we studied the function of IL10 in infection-associated intestinal inflammation. Methods: Wildtype mice and mice deficient in CD4+ T cell-derived or regulatory T cells-derived IL10 were infected with the enteric pathogen Citrobacter (C.) rodentium and analyzed for the specific immune response and pathogloy in the colon. Results: We found that IL10 expression is upregulated in colonic tissue after infection with C. rodentium, especially in CD4+ T cells, macrophages and dendritic cells. Whereas the deletion of IL10 in regulatory T cells had no effect on C. rodentium induced colitis, infection of mice deficient in CD4+ T cell-derived IL10 exhibited faster clearance of the bacterial burden but worse colitis, crypt hyperplasia, and pathology than did WT mice. In addition, the depletion of CD4+ T cell-derived IL10 in infected animals was accompanied by an accelerated IFNγ and IL17 response in the colon. Conclusion: Thus, we conclude that CD4+ T cell-derived IL10 is strongly involved in the control of C. rodentium-induced colitis. Interference with this network could have implications for the treatment of infection-associated intestinal inflammation.

scholarly journals Antigen-Specific TGF-β–Induced Regulatory T Cells Secrete Chemokines, Regulate T Cell Trafficking, and Suppress Ongoing Autoimmunity

2011 ◽  
Vol 187 (4) ◽  
pp. 1745-1753 ◽  
Author(s):  
Thanh-Long M. Nguyen ◽  
Nicole L. Sullivan ◽  
Mark Ebel ◽  
Ryan M. Teague ◽  
Richard J. DiPaolo
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Cell Trafficking ◽  
T Cell Trafficking

scholarly journals Egr2 and Egr3 in regulatory T cells cooperatively control systemic autoimmunity through Ltbp3-mediated TGF-β3 production

2016 ◽  
Vol 113 (50) ◽  
pp. E8131-E8140 ◽  
Author(s):  
Kaoru Morita ◽  
Tomohisa Okamura ◽  
Mariko Inoue ◽  
Toshihiko Komai ◽  
Shuzo Teruya ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Regulatory T Cells ◽  
Lupus Erythematosus ◽  
Mice Model ◽  
Mild Phenotype ◽  
Humoral Immune ◽  
Germinal Center Reaction ◽  
Systemic Autoimmunity ◽  
Deficient Mice

Systemic lupus erythematosus (SLE) is a prototypical autoimmune disease characterized by multiorgan inflammation induced by autoantibodies. Early growth response gene 2 (Egr2), a transcription factor essential for T-cell anergy induction, controls systemic autoimmunity in mice and humans. We have previously identified a subpopulation of CD4+ regulatory T cells, CD4+CD25−LAG3+ cells, that characteristically express both Egr2 and LAG3 and control mice model of lupus via TGF-β3 production. However, due to the mild phenotype of lymphocyte-specific Egr2-deficient mice, the presence of an additional regulator has been speculated. Here, we show that Egr2 and Egr3 expressed in T cells cooperatively prevent humoral immune responses by supporting TGF-β3 secretion. T cell-specific Egr2/Egr3 double-deficient (Egr2/3DKO) mice spontaneously developed an early onset lupus-like disease that was more severe than in T cell-specific Egr2-deficient mice. In accordance with the observation that CD4+CD25−LAG3+ cells from Egr2/3DKO mice completely lost the capacity to produce TGF-β3, the excessive germinal center reaction in Egr2/3DKO mice was suppressed by the adoptive transfer of WT CD4+CD25−LAG3+ cells or treatment with a TGF-β3–expressing vector. Intriguingly, latent TGF-β binding protein (Ltbp)3 expression maintained by Egr2 and Egr3 was required for TGF-β3 production from CD4+CD25−LAG3+ cells. Because Egr2 and Egr3 did not demonstrate cell intrinsic suppression of the development of follicular helper T cells, Egr2- and Egr3-dependent TGF-β3 production by CD4+CD25−LAG3+ cells is critical for controlling excessive B-cell responses. The unique attributes of Egr2/Egr3 in T cells may provide an opportunity for developing novel therapeutics for autoantibody-mediated diseases including SLE.

scholarly journals Microbiota innate stimulation is a prerequisite for T cell spontaneous proliferation and induction of experimental colitis

2010 ◽  
Vol 207 (6) ◽  
pp. 1321-1332 ◽  
Author(s):  
Ting Feng ◽  
Lanfang Wang ◽  
Trenton R. Schoeb ◽  
Charles O. Elson ◽  
Yingzi Cong
Keyword(s):  
Cell Proliferation ◽  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Experimental Colitis ◽  
Intestinal Lumen ◽  
T Cell Proliferation ◽  
Specific Pathogen ◽  
Spontaneous Proliferation ◽  
Cognate Antigen

Little is known about how the microbiota regulates T cell proliferation and whether spontaneous T cell proliferation is involved in the pathogenesis of inflammatory bowel disease. In this study, we show that stimulation of innate pathways by microbiota-derived ligands and antigen-specific T cell stimulation are both required for intestinal inflammation. Microbiota-derived ligands promoted spontaneous T cell proliferation by activating dendritic cells (DCs) to produce IL-6 via Myd88, as shown by the spontaneous proliferation of T cells adoptively transferred into specific pathogen–free (SPF) RAG−/− mice, but not in germfree RAG−/− mice. Reconstitution of germfree RAG−/− mice with cecal bacterial lysate–pulsed DCs, but not with IL-6−/− or Myd88−/− DCs, restored spontaneous T cell proliferation. CBir1 TCR transgenic (CBir1 Tg) T cells, which are specific for an immunodominant microbiota antigen, induced colitis in SPF RAG−/− mice. Blocking the spontaneous proliferation of CBir1 Tg T cells by co-transferring bulk OT II CD4+ T cells abrogated colitis development. Although transferred OT II T cells underwent spontaneous proliferation in RAG−/− mice, the recipients failed to develop colitis because of the lack of cognate antigen in the intestinal lumen. Collectively, our data demonstrate that induction of colitis requires both spontaneous proliferation of T cells driven by microbiota-derived innate signals and antigen-specific T cell proliferation.

scholarly journals Experimental colitis promotes sustained, sex-dependent, T-cell-associated neuroinflammation and parkinsonian neuropathology

2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Madelyn C. Houser ◽  
W. Michael Caudle ◽  
Jianjun Chang ◽  
George T. Kannarkat ◽  
Yuan Yang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Intestinal Inflammation ◽  
Specific Interaction ◽  
Experimental Colitis ◽  
Neurological Dysfunction ◽  
Male Mice ◽  
Dopaminergic Pathways ◽  
The Brain

Abstract Background The etiology of sporadic Parkinson’s disease (PD) remains uncertain, but genetic, epidemiological, and physiological overlap between PD and inflammatory bowel disease suggests that gut inflammation could promote dysfunction of dopamine-producing neurons in the brain. Mechanisms behind this pathological gut-brain effect and their interactions with sex and with environmental factors are not well understood but may represent targets for therapeutic intervention. Methods We sought to identify active inflammatory mechanisms which could potentially contribute to neuroinflammation and neurological disease in colon biopsies and peripheral blood immune cells from PD patients. Then, in mouse models, we assessed whether dextran sodium sulfate-mediated colitis could exert lingering effects on dopaminergic pathways in the brain and whether colitis increased vulnerability to a subsequent exposure to the dopaminergic neurotoxicant 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). We assessed the involvement of inflammatory mechanisms identified in the PD patients in colitis-related neurological dysfunction in male and female mice, utilizing mice lacking the Regulator of G-Protein Signaling 10 (RGS10)—an inhibitor of nuclear factor kappa B (NFκB)—to model enhanced NFκB activity, and mice in which CD8+ T-cells were depleted. Results High levels of inflammatory markers including CD8B and NFκB p65 were found in colon biopsies from PD patients, and reduced levels of RGS10 were found in immune cells in the blood. Male mice that experienced colitis exhibited sustained reductions in tyrosine hydroxylase but not in dopamine as well as sustained CD8+ T-cell infiltration and elevated Ifng expression in the brain. CD8+ T-cell depletion prevented colitis-associated reductions in dopaminergic markers in males. In both sexes, colitis potentiated the effects of MPTP. RGS10 deficiency increased baseline intestinal inflammation, colitis severity, and neuropathology. Conclusions This study identifies peripheral inflammatory mechanisms in PD patients and explores their potential to impact central dopaminergic pathways in mice. Our findings implicate a sex-specific interaction between gastrointestinal inflammation and neurologic vulnerability that could contribute to PD pathogenesis, and they establish the importance of CD8+ T-cells in this process in male mice. Graphical abstract

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