scholarly journals Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation

2015 ◽  
Vol 212 (11) ◽  
pp. 1869-1882 ◽  
Author(s):  
Christina Song ◽  
Jacob S. Lee ◽  
Susan Gilfillan ◽  
Michelle L. Robinette ◽  
Rodney D. Newberry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Inflammation ◽  
Gm Csf ◽  
Aryl Hydrocarbon ◽  
Inflammatory Monocytes ◽  
Group 3 ◽  
Redundant Functions ◽  
Deficient Mice ◽  
Colitis Model

Group 3 ILCs (ILC3s) are innate sources of IL-22 and IL-17 and include lymphoid tissue-inducer (LTi)-like and NKp46+ subsets. Both depend on RORγt and aryl hydrocarbon receptor, but NKp46+ILC3s also require Notch and T-bet for their development and are transcriptionally distinct. The extent to which these subsets have unique functions, especially in the context of T cell– and B cell–sufficient mice, remains largely unclear. To investigate the specific function of NKp46+ILC3s among other ILC3 subsets and T cells, we generated mice selectively lacking NKp46+ILC3s or all ILC3s and crossed them to T cell–deficient mice, thus maintaining B cells in all mice. In mice lacking T cells, NKp46+ILC3s were sufficient to promote inflammatory monocyte accumulation in the anti-CD40 innate colitis model through marked production of GM-CSF. In T cell–competent mice, lack of NKp46+ILCs had no impact on control of intestinal C. rodentium infection, whereas lack of all ILC3s partially impaired bacterial control. Thus, NKp46+ILC3s have a unique capacity to promote inflammation through GM-CSF–induced accumulation of inflammatory monocytes, but are superseded by LTi-like ILC3s and T cells in controlling intestinal bacterial infection.

scholarly journals The Group 3 Innate Lymphoid Cell Defect in Aryl Hydrocarbon Receptor Deficient Mice Is Associated with T Cell Hyperactivation during Intestinal Infection

PLoS ONE ◽  
2015 ◽  
Vol 10 (5) ◽  
pp. e0128335 ◽  
Author(s):  
Sagie Wagage ◽  
Gretchen Harms Pritchard ◽  
Lucas Dawson ◽  
Elizabeth L. Buza ◽  
Gregory F. Sonnenberg ◽  
...  
Keyword(s):  
T Cell ◽  
Aryl Hydrocarbon Receptor ◽  
Lymphoid Cell ◽  
Intestinal Infection ◽  
Innate Lymphoid Cell ◽  
Aryl Hydrocarbon ◽  
Group 3 ◽  
Deficient Mice ◽  
Cell Defect

scholarly journals MAIT cells promote inflammatory monocyte differentiation into dendritic cells during pulmonary intracellular infection

2016 ◽  
Vol 213 (12) ◽  
pp. 2793-2809 ◽  
Author(s):  
Anda I. Meierovics ◽  
Siobhán C. Cowley
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Cell Subset ◽  
Monocyte Differentiation ◽  
Gm Csf ◽  
Mait Cells ◽  
Inflammatory Monocytes ◽  
Deficient Mice ◽  
Mait Cell ◽  
Csf Production

Mucosa-associated invariant T (MAIT) cells are a unique innate T cell subset that is necessary for rapid recruitment of activated CD4+ T cells to the lungs after pulmonary F. tularensis LVS infection. Here, we investigated the mechanisms behind this effect. We provide evidence to show that MAIT cells promote early differentiation of CCR2-dependent monocytes into monocyte-derived DCs (Mo-DCs) in the lungs after F. tularensis LVS pulmonary infection. Adoptive transfer of Mo-DCs to MAIT cell–deficient mice (MR1−/− mice) rescued their defect in the recruitment of activated CD4+ T cells to the lungs. We further demonstrate that MAIT cell–dependent GM-CSF production stimulated monocyte differentiation in vitro, and that in vivo production of GM-CSF was delayed in the lungs of MR1−/− mice. Finally, GM-CSF–deficient mice exhibited a defect in monocyte differentiation into Mo-DCs that was phenotypically similar to MR1−/− mice. Overall, our data demonstrate that MAIT cells promote early pulmonary GM-CSF production, which drives the differentiation of inflammatory monocytes into Mo-DCs. Further, this delayed differentiation of Mo-DCs in MR1−/− mice was responsible for the delayed recruitment of activated CD4+ T cells to the lungs. These findings establish a novel mechanism by which MAIT cells function to promote both innate and adaptive immune responses.

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.

scholarly journals Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

2017 ◽  
Vol 114 (36) ◽  
pp. E7536-E7544 ◽  
Author(s):  
Soyoung A. Oh ◽  
Ming Liu ◽  
Briana G. Nixon ◽  
Davina Kang ◽  
Ahmed Toure ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Autoimmune Diabetes ◽  
Treg Cells ◽  
T Cell Tolerance ◽  
Cell Tolerance ◽  
Gm Csf ◽  
Complete Penetrance ◽  
Inflammatory Monocytes ◽  
Β Receptor

Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

scholarly journals The neutrophil antimicrobial peptide cathelicidin promotes Th17 differentiation

2020 ◽  
Author(s):  
Danielle Minns ◽  
Katie J Smith ◽  
Virginia Alessandrini ◽  
Gareth Hardisty ◽  
Lauren Melrose ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Cell Phenotype ◽  
Dependent Manner ◽  
Adaptive Immune ◽  
Aryl Hydrocarbon ◽  
Th17 Differentiation ◽  
Deficient Mice ◽  
Tgf Β1

ABSTRACTThe host defence peptide cathelicidin (LL-37 in humans, mCRAMP in mice) is released from neutrophils by de-granulation, NETosis and necrotic cell death; it has potent antibacterial, antiviral and antifungal activity as well as being a powerful immunomodulator. It is released in proximity to CD4+ T cells during inflammatory and infectious disease but its impact on T cell phenotype is scarcely understood. Here we demonstrate that cathelicidin is a powerful Th17 potentiating factor which increases expression of the aryl hydrocarbon receptor (AHR) and the RORγt transcription factor, in a TGF-β1-dependent manner. We show that cathelicidin induces IL-17F production in particular, and that its induction of IL-17A+F+ double producing cells is dependent on AHR while its induction of IL-17F single producing cells is not. In the presence of TGF-β1, cathelicidin profoundly suppressed IL-2 and down-regulated T-bet, specifically directing T cells away from Th1 and into a Th17 phenotype. Strikingly, Th17, but not Th1 cells were protected from apoptotic death by cathelicidin, in the first example of a neutrophil-released mediator inducing survival of a T cell subset. Finally, we show that cathelicidin is released by neutrophils in mouse lymph nodes following inoculation of heat-killed Salmonella typhimurium and that cathelicidin-deficient mice have suppressed Th17 responses during inflammation, but not at steady state. We propose that the release of cathelicidin by neutrophils is required for maximal Th17 differentiation and IL-17 production by CD4+ T cells, and that this is one method by which early neutrophilia directs subsequent adaptive immune responses with some sophistication.

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.

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