scholarly journals STAT6 Signaling Attenuates Interleukin-17-Producing γδ T Cells during Acute Klebsiella pneumoniae Infection

2016 ◽  
Vol 84 (5) ◽  
pp. 1548-1555 ◽  
Author(s):  
Melissa H. Bloodworth ◽  
Dawn C. Newcomb ◽  
Daniel E. Dulek ◽  
Matthew T. Stier ◽  
Jacqueline Y. Cephus ◽  
...  
Keyword(s):  
T Cells ◽  
Klebsiella Pneumoniae ◽  
Fungal Pathogens ◽  
Γδ T Cells ◽  
Parasitic Infections ◽  
Interleukin 17 ◽  
Type I ◽  
Content Type ◽  
Antibacterial And Antifungal

γδ T cells are prevalent at mucosal and epithelial surfaces and are a critical first line of defense against bacterial and fungal pathogens. γδ17 cells are a subset of γδ T cells which, in the presence of IL-23 and IL-1β, produce large quantities of interleukin-17A (IL-17A), a cytokine crucial to these cells' antibacterial and antifungal function. STAT6, an important transcription factor in Th2 differentiation and inhibition of Th1 differentiation, is expressed at high levels in the T cells of people with parasitic infections and asthma. Our group and others have shown that STAT6 attenuates IL-17A protein expression by CD4+T cells. By extension, we hypothesized that STAT6 activation also inhibits innate γδ17 cell cytokine secretion. We show here that γδ17 cells expressed the type I IL-4 receptor (IL-4R), and IL-4 increased STAT6 phosphorylation in γδ T cells. IL-4 inhibited γδ17 cell production of IL-17A. IL-4 also decreased γδ17 cell expression of IL-23R as well as Sgk1. To determine whether STAT6 signaling regulates γδ17 cell numbersin vivo, we used a model ofKlebsiella pneumoniaein mice deficient in STAT6. We choseK. pneumoniaefor ourin vivomodel, sinceK. pneumoniaeincreases IL-17A expression and γδ17 numbers.K. pneumoniaeinfection of STAT6 knockout mice resulted in a statistically significant increase in the number of γδ17 cells compared to that of wild-type mice. These studies are the first to demonstrate that γδ17 cells express the type I IL-4R and that STAT6 signaling negatively regulates γδ17 cells, a cell population that plays a front-line role in mucosal immunity.

scholarly journals Pulmonary Interleukin-17-Positive Lymphocytes Increase during Pneumocystis murina Infection but Are Not Required for Clearance of Pneumocystis

2017 ◽  
Vol 85 (7) ◽  
Author(s):  
Chiara Ripamonti ◽  
Lisa R. Bishop ◽  
Joseph A. Kovacs
Keyword(s):  
T Cells ◽  
Fungal Infections ◽  
Intracellular Cytokine Staining ◽  
Γδ T Cells ◽  
Interleukin 17 ◽  
Content Type ◽  
Immunosuppressed Patients ◽  
Ifn Γ ◽  
Immunocompetent Mice ◽  
Deficient Mice

ABSTRACT Pneumocystis remains an important pathogen of immunosuppressed patients, causing a potentially life-threatening pneumonia. Despite its medical importance, the immune responses required to control infection, including the role of interleukin-17 (IL-17), which is important in controlling other fungal infections, have not been clearly defined. Using flow cytometry and intracellular cytokine staining after stimulation with phorbol myristate acetate and ionomycin, we examined gamma interferon (IFN-γ), IL-4, IL-5, and IL-17 production by lung lymphocytes in immunocompetent C57BL/6 mice over time following infection with Pneumocystis murina. We also examined the clearance of Pneumocystis infection in IL-17A-deficient mice. The production of both IFN-γ and IL-17 by pulmonary lymphocytes increased during infection, with maximum production at approximately days 35 to 40, coinciding with peak Pneumocystis levels in the lungs, while minimal changes were seen in IL-4- and IL-5-positive cells. The proportion of cells producing IFN-γ was consistently higher than for cells producing IL-17, with peak levels of ∼25 to 30% of CD3+ T cells for the former compared to ∼15% for the latter. Both CD4+ T cells and γδ T cells produced IL-17. Administration of anti-IFN-γ antibody led to a decrease in IFN-γ-positive cells, and an increase in IL-5-positive cells, but did not impact clearance of Pneumocystis infection. Despite the increases in IL-17 production during infection, IL-17A-deficient mice cleared Pneumocystis infection with kinetics similar to C57BL/6 mice. Thus, while IL-17 production in the lungs is increased during Pneumocystis infection in immunocompetent mice, IL-17A is not required for control of Pneumocystis infection.

scholarly journals Reduced Immune Response to Borrelia burgdorferi in the Absence of γδ T Cells

2011 ◽  
Vol 79 (10) ◽  
pp. 3940-3946 ◽  
Author(s):  
Cuixia Shi ◽  
Bikash Sahay ◽  
Jennifer Q. Russell ◽  
Karen A. Fortner ◽  
Nicholas Hardin ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Borrelia Burgdorferi ◽  
Adaptive Immune Response ◽  
Γδ T Cells ◽  
Content Type ◽  
Adaptive Immune ◽  
Cytokines And Chemokines

ABSTRACTLittle is known regarding the function of γδ T cells, although they accumulate at sites of inflammation in infections and autoimmune disorders. We previously observed that γδ T cellsin vitroare activated byBorrelia burgdorferiin a TLR2-dependent manner. We now observe that the activated γδ T cells can in turn stimulate dendritic cellsin vitroto produce cytokines and chemokines that are important for the adaptive immune response. This suggested thatin vivoγδ T cells may assist in activating the adaptive immune response. We examined this possibilityin vivoand observed that γδ T cells are activated and expand in number duringBorreliainfection, and this was reduced in the absence of TLR2. Furthermore, in the absence of γδ T cells, there was a significantly blunted response of adaptive immunity, as reflected in reduced expansion of T and B cells and reduced serum levels of anti-Borreliaantibodies, cytokines, and chemokines. This paralleled a greaterBorreliaburden in γδ-deficient mice as well as more cardiac inflammation. These findings are consistent with a model of γδ T cells functioning to promote the adaptive immune response during infection.

scholarly journals Recruitment of Neutrophils Mediated by Vγ2 γδ T Cells Deteriorates Liver Fibrosis Induced by Schistosoma japonicum Infection in C57BL/6 Mice

2017 ◽  
Vol 85 (8) ◽  
Author(s):  
Li Zheng ◽  
Yuan Hu ◽  
Yanjuan Wang ◽  
Xibao Huang ◽  
Yuxin Xu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Liver Fibrosis ◽  
Schistosoma Japonicum ◽  
Γδ T Cells ◽  
T Cell Subsets ◽  
Interleukin 17 ◽  
Content Type ◽  
Ifn Γ

ABSTRACT Conventional adaptive T cell responses contribute to the pathogenesis of Schistosoma japonicum infection, leading to liver fibrosis. However, the role of gamma-delta (γδ) T cells in this disease is less clear. γδ T cells are known to secrete interleukin-17 (IL-17) in response to infection, exerting either protective or pathogenic functions. In the present study, mice infected with S. japonicum are used to characterize the role of γδ T cells. Combined with the infection of S. japonicum, an extremely significant increase in the percentage of neutrophils in the CD45+ cells was detected (from approximately 2.45% to 46.10% in blood and from 0.18% to 7.34% in spleen). Further analysis identified two different γδ T cell subsets that have different functions in the formation of granulomas in S. japonicum-infected mice. The Vγ1 T cells secrete gamma interferon (IFN-γ) only, while the Vγ2 T cells secrete both IL-17A and IFN-γ. Both subtypes lose the ability to secrete cytokine during the late stage of infection (12 weeks postinfection). When we depleted the Vγ2 T cells in infected mice, the percentage of neutrophils in blood and spleen decreased significantly, the liver fibrosis in the granulomas was reduced, and the level of IL-17A in the serum decreased (P < 0.05). These results suggest that during S. japonicum infection, Vγ2 T cells can recruit neutrophils and aggravate liver fibrosis by secreting IL-17A. This is the first report that a subset of γδ T cells plays a partial role in the pathological process of schistosome infection.

scholarly journals A Theileria parva Isolate of Low Virulence Infects a Subpopulation of Lymphocytes

2011 ◽  
Vol 80 (3) ◽  
pp. 1267-1273 ◽  
Author(s):  
Heshborne S. Tindih ◽  
Dirk Geysen ◽  
Bruno M. Goddeeris ◽  
Elias Awino ◽  
Dirk A. E. Dobbelaere ◽  
...  
Keyword(s):  
T Cells ◽  
Mononuclear Cells ◽  
Γδ T Cells ◽  
Target Cells ◽  
Theileria Parva ◽  
Logarithmic Growth Phase ◽  
Peripheral Blood Mononuclear ◽  
Content Type

Theileria parvais a tick-transmitted protozoan parasite that infects and transforms bovine lymphocytes. We have previously shown thatTheileria parvaChitongo is an isolate with a lower virulence than that ofT. parvaMuguga. Lower virulence appeared to be correlated with a delayed onset of the logarithmic growth phase ofT. parvaChitongo-transformed peripheral blood mononuclear cells afterin vitroinfection. In the current study, infection experiments with WC1+γδ T cells revealed that onlyT. parvaMuguga could infect these cells and that no transformed cells could be obtained withT. parvaChitongo sporozoites. Subsequent analysis of the susceptibility of different cell lines and purified populations of lymphocytes to infection and transformation by both isolates showed thatT. parvaMuguga sporozoites could attach to and infect CD4+, CD8+, and WC1+T lymphocytes, butT. parvaChitongo sporozoites were observed to bind only to the CD8+T cell population. Flow cytometry analysis of established, transformed clones confirmed this bias in target cells.T. parvaMuguga-transformed clones consisted of different cell surface phenotypes, suggesting that they were derived from either host CD4+, CD8+, or WC1+T cells. In contrast, allin vitroandin vivoT. parvaChitongo-transformed clones expressed CD8 but not CD4 or WC1, suggesting that theT. parvaChitongo-transformed target cells were exclusively infected CD8+lymphocytes. Thus, a role of cell tropism in virulence is likely. Since the adhesion molecule p67 is 100% identical between the two strains, a second, high-affinity adhesin that determines target cell specificity appears to exist.

scholarly journals CD30 Is Required for Activation of a Unique Subset of Interleukin-17A-Producing γδ T Cells in Innate Immunity against Mycobacterium bovis Bacillus Calmette-Guérin Infection

2013 ◽  
Vol 81 (10) ◽  
pp. 3923-3934 ◽  
Author(s):  
Ying Guo ◽  
Xun Sun ◽  
Kensuke Shibata ◽  
Hisakata Yamada ◽  
Hiromi Muta ◽  
...  
Keyword(s):  
T Cells ◽  
Mycobacterium Bovis ◽  
Early Stage ◽  
Γδ T Cells ◽  
Bacillus Calmette Guerin ◽  
Content Type ◽  
Interleukin 17A ◽  
Soluble Cd30 ◽  
Infection Inhibition

ABSTRACTInterleukin-17A (IL-17A)-producing γδ T cells are known to be activated followingMycobacterium bovisbacillus Calmette-Guérin (BCG) infection. Here, we show that CD30, a member of the tumor necrosis factor (TNF) receptor superfamily, is important for activation of IL-17A-producing γδ T cells after BCG infection. Vγ1−Vγ4−γδ T cells preferentially expressing Vγ6/Vδ1 genes were identified as the major source of IL-17A in the peritoneal cavity during the early stage of BCG infection. The number of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 increased in peritoneal exudate cells (PEC) of wild-type (WT) mice but not in those of CD30 knockout (KO) mice in response to BCG infection. Consistently, CD30 ligand (CD30L) or CD30 expression, predominantly by Vγ1−Vγ4−γδ T cells, was rapidly upregulated after BCG infection. Inhibition of CD30L/CD30 signaling byin vivoadministration of a soluble CD30 and immunoglobulin fusion protein (CD30-Ig) severely impaired activation of IL-17A-producing Vγ1−Vγ4−γδ T cells in WT mice, while stimulating CD30L/CD30 signaling byin vivoadministration of agonistic anti-CD30 monoclonal antibody (MAb) restored IL-17A production by Vγ1−Vγ4−γδ T cells in CD30L KO mice after BCG infection. These results suggest that CD30 signaling plays an important role in the activation of IL-17A-producing Vγ1−Vγ4−γδ T cells bearing Vγ6 at an early stage of BCG infection.

scholarly journals Development of a new monoclonal antibody specific to mouse Vγ6 chain

2019 ◽  
Vol 2 (3) ◽  
pp. e201900363 ◽  
Author(s):  
Shinya Hatano ◽  
Xin Tun ◽  
Naoto Noguchi ◽  
Dan Yue ◽  
Hisakata Yamada ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
T Cells ◽  
Monoclonal Antibodies ◽  
Klebsiella Pneumoniae ◽  
Γδ T Cells ◽  
Cell Surface Staining ◽  
Surface Staining ◽  
In Vivo Administration ◽  
Complementarity Determining Region

There are seven Vγ gene segments in the TCR γ chain loci of mice. We developed monoclonal antibodies (mAbs) specific to the Vγ6 chain (Heilig & Tonegawa nomenclature). By immunizing Vγ4/6 KO mice with complementarity-determining region peptides in Vγ6 chains, we generated three hybridomas. These hybridomas produced mAbs capable of cell surface staining of Vγ6/Vδ1 gene–transfected T-cell line lacking TCR as well as of Vγ1− Vγ4− Vγ5− Vγ7− γδ T cells and the CD3high TCRδint γδ T cells in various organs. The location of Vγ6+ γδ T cells, which peaked in the newborn thymus, was associated with mTEC. In vivo administration of clone 1C10-1F7 mAb impaired protection against Klebsiella pneumoniae infection but ameliorated psoriasis-like dermatitis induced by imiquimod treatment. These new mAbs are useful to elucidate the development, location, and functions of Vγ6 γδ T cells in mice.

scholarly journals Role of CD4+Foxp3+Regulatory T Cells in Protection Induced by a Live Attenuated, Replicating Type I Vaccine Strain of Toxoplasma gondii

2015 ◽  
Vol 83 (9) ◽  
pp. 3601-3611 ◽  
Author(s):  
Haroon Akbar ◽  
Isabelle Dimier-Poisson ◽  
Nathalie Moiré
Keyword(s):  
T Cells ◽  
Toxoplasma Gondii ◽  
Regulatory T Cells ◽  
T Regulatory Cells ◽  
Interleukin 2 ◽  
Type I ◽  
Content Type ◽  
Effector Cells ◽  
Cytokine Responses

Vaccination with the live attenuatedToxoplasma gondiiMic1.3KO strain induced long-lasting immunity against challenge withToxoplasma gondiitype I and type II strains. The involvement of regulatory T cells (Tregs) in the protection mechanism was investigated. Intraperitoneal injection of Mic1.3KO induced a weak and transient influx of CD4+Foxp3+T regulatory cells followed by recruitment/expansion of CD4+Foxp3−CD25+effector cells and control of the parasite at the site of infection. The local and systemic cytokine responses associated with this recruitment of Tregs were of the TH1/Treg-like type. In contrast, injection of RH, the wild-type strain from which the vaccinal strain is derived, induced a low CD4+Foxp3+cell influx and uncontrolled multiplication of the parasites at this local site, followed by death of the mice. The associated local and systemic cytokine responses were of the TH1/TH17-like type. In addition,in vivoTreg induction in RH-infected mice with interleukin-2 (IL-2)/anti-IL-2 complexes induced control of the parasite and a TH1/Treg cytokine response similar to the response after Mic1.3KO vaccination. These results suggest that Tregs may contribute to the protective response after vaccination with Mic1.3KO.

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