scholarly journals Interleukin-23 Orchestrates Mucosal Responses to Salmonella enterica Serotype Typhimurium in the Intestine

2008 ◽  
Vol 77 (1) ◽  
pp. 387-398 ◽  
Author(s):  
Ivan Godinez ◽  
Manuela Raffatellu ◽  
Hiutung Chu ◽  
Tatiane A. Paixão ◽  
Takeshi Haneda ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intestinal Mucosa ◽  
Salmonella Enterica ◽  
Inflammatory Responses ◽  
Γδ T Cells ◽  
Wild Type ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Cecal Mucosa

ABSTRACT Salmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the ceca of streptomycin-pretreated mice that involves T-cell-dependent induction of gamma interferon (IFN-γ), interleukin-22 (IL-22), and IL-17 expression (genes Ifn-γ, Il-22, and Il-17, respectively). We investigated here the role of IL-23 in initiating these inflammatory responses using the streptomycin-pretreated mouse model. Compared to wild-type mice, the expression of IL-17 was abrogated, IL-22 expression was markedly reduced, but IFN-γ expression was normal in the ceca of IL-23p19-deficient mice during serotype Typhimurium infection. IL-23p19-deficient mice also exhibited a markedly reduced expression of regenerating islet-derived 3 gamma, keratinocyte-derived cytokine, and reduced neutrophil recruitment into the cecal mucosa during infection. Analysis of CD3+ lymphocytes in the intestinal mucosa by flow cytometry revealed that αβ T cells were the predominant cell type expressing the IL-23 receptor in naive mice. However, a marked increase in the number of IL-23 receptor-expressing γδ T cells was observed in the lamina propria during serotype Typhimurium infection. Compared to wild-type mice, γδ T-cell-receptor-deficient mice exhibited blunted expression of IL-17 during serotype Typhimurium infection, while IFN-γ expression was normal. These data suggested that γδ T cells are a significant source, but not the sole source, of IL-17 in the acutely inflamed cecal mucosa of mice. Collectively, our results point to IL-23 as an important player in initiating a T-cell-dependent amplification of inflammatory responses in the intestinal mucosa during serotype Typhimurium infection.

scholarly journals T Cell-Independent Gamma Interferon and B Cells Cooperate To Prevent Mortality Associated with DisseminatedChlamydia muridarumGenital Tract Infection

2018 ◽  
Vol 86 (7) ◽  
pp. e00143-18 ◽  
Author(s):  
Taylor B. Poston ◽  
Catherine M. O'Connell ◽  
Jenna Girardi ◽  
Jeanne E. Sullivan ◽  
Uma M. Nagarajan ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Tract Infection ◽  
B Cell ◽  
Gamma Interferon ◽  
Wild Type ◽  
Content Type ◽  
Ifn Γ ◽  
Deficient Mice

ABSTRACTCD4 T cells and antibody are required for optimal acquired immunity toChlamydia muridarumgenital tract infection, and T cell-mediated gamma interferon (IFN-γ) production is necessary to clear infection in the absence of humoral immunity. However, the role of T cell-independent immune responses during primary infection remains unclear. We investigated this question by inoculating wild-type and immune-deficient mice withC. muridarumCM001, a clonal isolate capable of enhanced extragenital replication. Genital inoculation of wild-type mice resulted in transient dissemination to the lungs and spleen that then was rapidly cleared from these organs. However, CM001 genital infection proved lethal forSTAT1−/−andIFNG−/−mice, in which IFN-γ signaling was absent, and forRag1−/−mice, which lacked T and B cells and in which innate IFN-γ signaling was retained. In contrast, B cell-deficient muMT mice, which can generate a Th1 response, and T cell-deficient mice with intact B cell and innate IFN-γ signaling survived. These data collectively indicate that IFN-γ prevents lethal CM001 dissemination in the absence of T cells and suggests a B cell corequirement. Adoptive transfer of convalescent-phase immune serum but not naive IgM toRag1−/−mice infected with CM001 significantly increased the survival time, while transfer of naive B cells completely rescuedRag1−/−mice from CM001 lethality. Protection was associated with a significant reduction in the lung chlamydial burden of genitally infected mice. These data reveal an important cooperation between T cell-independent B cell responses and innate IFN-γ in chlamydial host defense and suggest that interactions between T cell-independent antibody and IFN-γ are essential for limiting extragenital dissemination.

scholarly journals T Cells Help To Amplify Inflammatory Responses Induced by Salmonella enterica Serotype Typhimurium in the Intestinal Mucosa

2008 ◽  
Vol 76 (5) ◽  
pp. 2008-2017 ◽  
Author(s):  
Ivan Godinez ◽  
Takeshi Haneda ◽  
Manuela Raffatellu ◽  
Michael D. George ◽  
Tatiane A. Paixão ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Gene Expression Profile ◽  
Expression Profile ◽  
Salmonella Enterica ◽  
Inflammatory Responses ◽  
Mrna Levels ◽  
Genes Encoding ◽  
Ifn Γ ◽  
Cecal Mucosa

ABSTRACT Salmonella enterica serotype Typhimurium causes an acute inflammatory reaction in the ceca of streptomycin-pretreated mice. We determined global changes in gene expression elicited by serotype Typhimurium in the cecal mucosa. The gene expression profile was dominated by T-cell-derived cytokines and genes whose expression is known to be induced by these cytokines. Markedly increased mRNA levels of genes encoding gamma interferon (IFN-γ), interleukin-22 (IL-22), and IL-17 were detected by quantitative real-time PCR. Furthermore, the mRNA levels of genes whose expression is induced by IFN-γ, IL-22, or IL-17, including genes encoding macrophage inflammatory protein 2 (MIP-2), inducible nitric oxide synthase (Nos2), lipocalin-2 (Lcn2), MIP-1α, MIP-1β, and keratinocyte-derived cytokine (KC), were also markedly increased. To assess the importance of T cells in orchestrating this proinflammatory gene expression profile, we depleted T cells by using a monoclonal antibody prior to investigating cecal inflammation caused by serotype Typhimurium in streptomycin-pretreated mice. Depletion of CD3+ T cells resulted in a dramatic reduction in gross pathology, a significantly reduced recruitment of neutrophils, and a marked reduction in mRNA levels of Ifn-γ, Il-22, Il-17, Nos2, Lcn2, and Kc. Our results suggest that T cells play an important role in amplifying inflammatory responses induced by serotype Typhimurium in the cecal mucosa.

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 Distinct contributions of CD4+ T cell subsets in hepatic ischemia/reperfusion injury

2009 ◽  
Vol 296 (5) ◽  
pp. G1054-G1059 ◽  
Author(s):  
Satoshi Kuboki ◽  
Nozomu Sakai ◽  
Johannes Tschöp ◽  
Michael J. Edwards ◽  
Alex B. Lentsch ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nk Cells ◽  
Ischemia Reperfusion ◽  
Γδ T Cells ◽  
Nkt Cells ◽  
T Cell Subsets ◽  
Wild Type ◽  
Hepatic Ischemia ◽  
Hepatic Ischemia Reperfusion

Helper T cells are known to mediate hepatic ischemia/reperfusion (I/R) injury. However, the precise mechanisms and subsets of CD4+ T cells that contribute to this injury are still controversial. Therefore, we sought to determine the contributions of different CD4+ T cell subsets during hepatic I/R injury. Wild-type, OT-II, or T cell receptor (TCR)-δ-deficient mice were subjected to 90 min of partial hepatic ischemia followed by 8 h of reperfusion. Additionally, wild-type mice were pretreated with anti-CD1d, -NK1.1, or -IL-2R-α antibodies before I/R injury. OT-II mice had diminished liver injury compared with wild-type mice, implicating that antigen-dependent activation of CD4+ T cells through TCRs is involved in hepatic I/R injury. TCR-δ knockout mice had decreased hepatic neutrophil accumulation, suggesting that γδ T cells regulate neutrophil recruitment. We found that natural killer T (NKT) cells, but not NK cells, contribute to hepatic I/R injury via CD1d-dependent activation of their TCRs, as depletion of NKT cells by anti-CD1d antibody or depletion of both NKT cells and NK cells by anti-NK1.1 attenuated liver injury. Although regulatory T cells (Treg) are known to suppress T cell-dependent inflammation, depletion of Treg cells had little effect on hepatic I/R injury. The data suggest that antigen-dependent activation of CD4+ T cells contributes to hepatic I/R injury. Among the subsets of CD4+ T cells, it appears that γδ T cells contribute to neutrophil recruitment and that NKT cells directly injure the liver. In contrast, NK cells and Treg have little effects on hepatic I/R injury.

CD56+ human blood dendritic cells effectively promote TH1-type γδ T-cell responses

Blood ◽  
2009 ◽  
Vol 114 (20) ◽  
pp. 4422-4431 ◽  
Author(s):  
Georg Gruenbacher ◽  
Hubert Gander ◽  
Andrea Rahm ◽  
Walter Nussbaumer ◽  
Nikolaus Romani ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Human Blood ◽  
Γδ T Cells ◽  
Rapid Expansion ◽  
Γδ T Cell ◽  
Hla Dr ◽  
Tnf Α ◽  
Ifn Γ

Abstract CD56+ human dendritic cells (DCs) have recently been shown to differentiate from monocytes in response to GM-CSF and type 1 interferon in vitro. We show here that CD56+ cells freshly isolated from human peripheral blood contain a substantial subset of CD14+CD86+HLA-DR+ cells, which have the appearance of intermediate-sized lymphocytes but spontaneously differentiate into enlarged DC-like cells with substantially increased HLA-DR and CD86 expression or into fully mature CD83+ DCs in response to appropriate cytokines. Stimulation of CD56+ cells containing both DCs and abundant γδ T cells with zoledronate and interleukin-2 (IL-2) resulted in the rapid expansion of γδ T cells as well as in IFN-γ, TNF-α, and IL-1β but not in IL-4, IL-10, or IL-17 production. IFN-γ, TNF-α, and IL-1β production were almost completely abolished by depleting CD14+ cells from the CD56+ subset before stimulation. Likewise, depletion of CD14+ cells dramatically impaired γδ T-cell expansion. IFN-γ production could also be blocked by neutralizing the effects of endogenous IL-1β and TNF-α. Conversely, addition of recombinant IL-1β, TNF-α, or both further enhanced IFN-γ production and strongly up-regulated IL-6 production. Our data indicate that CD56+ DCs from human blood are capable of stimulating CD56+ γδ T cells, which may be harnessed for immunotherapy.

scholarly journals Gamma Interferon Production, but Not Perforin-Mediated Cytolytic Activity, of T Cells Is Required for Prevention of Toxoplasmic Encephalitis in BALB/c Mice Genetically Resistant to the Disease

2004 ◽  
Vol 72 (8) ◽  
pp. 4432-4438 ◽  
Author(s):  
Xisheng Wang ◽  
Hoil Kang ◽  
Takane Kikuchi ◽  
Yasuhiro Suzuki
Keyword(s):  
T Cells ◽  
T Cell ◽  
Nude Mice ◽  
Genetic Resistance ◽  
Cytolytic Activity ◽  
Gamma Interferon ◽  
Toxoplasmic Encephalitis ◽  
Wild Type ◽  
Ifn Γ

ABSTRACT We previously showed the requirement of both T cells and gamma interferon (IFN-γ)-producing non-T cells for the genetic resistance of BALB/c mice to the development of toxoplasmic encephalitis (TE). In order to define the role of IFN-γ production and the perforin-mediated cytotoxicity of T cells in this resistance, we obtained immune T cells from spleens of infected IFN-γ knockout (IFN-γ−/−), perforin knockout (PO), and wild-type BALB/c mice and transferred them into infected and sulfadiazine-treated athymic nude mice, which lack T cells but have IFN-γ-producing non-T cells. Control nude mice that had not received any T cells developed severe TE and died after discontinuation of sulfadiazine treatment due to the reactivation of infection. Animals that had received immune T cells from either wild-type or PO mice did not develop TE and survived. In contrast, nude mice that had received immune T cells from IFN-γ−/− mice developed severe TE and died as early as control nude mice. T cells obtained from the spleens of animals that had received either PO or wild-type T cells produced large amounts of IFN-γ after stimulation with Toxoplasma gondii antigens in vitro. In addition, the amounts of IFN-γ mRNA expressed in the brains of PO T-cell recipients did not differ from those in wild-type T-cell recipients. Furthermore, PO mice did not develop TE after infection, and their IFN-γ production was equivalent to or higher than that of wild-type animals. These results indicate that IFN-γ production, but not perforin-mediated cytotoxic activity, by T cells is required for the prevention of TE in genetically resistant BALB/c mice.

scholarly journals Combination Treatment of Topical Imiquimod Plus Anti-PD-1 Antibody Exerts Significantly Potent Antitumor Effect

Cancers ◽  
2021 ◽  
Vol 13 (16) ◽  
pp. 3948
Author(s):  
Kazumasa Oya ◽  
Yoshiyuki Nakamura ◽  
Zhu Zhenjie ◽  
Ryota Tanaka ◽  
Naoko Okiyama ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Combination Therapy ◽  
T Cell Activation ◽  
Cd8 T Cells ◽  
Cell Activation ◽  
Antitumor Effect ◽  
Skin Lesions ◽  
Ifn Γ ◽  
Deficient Mice

The exact mechanisms of the imiquimod (IMQ)-induced antitumor effect have not been fully understood. Although both topical IMQ treatment and anti-PD-1 antibody may be used for primary skin lesions or skin metastases of various cancers, the efficacy of each monotherapy for these lesions is insufficient. Using a murine tumor model and human samples, we aimed to elucidate the detailed mechanisms of the IMQ-induced antitumor effect and analyzed the antitumor effect of combination therapy of topical IMQ plus anti-PD-1 antibody. Topical IMQ significantly suppressed the tumor growth of MC38 in wildtype mice. IMQ upregulated interferon γ (IFN-γ) expression in CD8+ T cells in both the lymph nodes and the tumor, and the antitumor effect was abolished in both Rag1-deficient mice and IFN-γ-deficient mice, indicating that IFN-γ produced by CD8+ T cells play a crucial role in the IMQ-induced antitumor effect. IMQ also upregulated PD-1 expression in T cells as well as PD-L1/PD-L2 expression in myeloid cells, suggesting that IMQ induces not only T-cell activation but also T-cell exhaustion by enhanced PD-1 inhibitory signaling. Combination therapy of topical IMQ plus anti-PD-1 antibody exerted a significantly potent antitumor effect when compared with each single therapy, indicating that the combination therapy is a promising therapy for the skin lesions of various cancers.

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.

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 T Cell Receptor Specificity Is Critical for the Development of Epidermal γδ T Cells

2001 ◽  
Vol 194 (10) ◽  
pp. 1473-1483 ◽  
Author(s):  
Isabel Ferrero ◽  
Anne Wilson ◽  
Friedrich Beermann ◽  
Werner Held ◽  
H. Robson MacDonald
Keyword(s):  
T Cells ◽  
T Cell ◽  
T Cell Receptor ◽  
Cell Biology ◽  
Γδ T Cells ◽  
Cell Receptor ◽  
Wild Type ◽  
Normal Numbers ◽  
T Cell Biology

A particular feature of γδ T cell biology is that cells expressing T cell receptor (TCR) using specific Vγ/Vδ segments are localized in distinct epithelial sites, e.g., in mouse epidermis nearly all γδ T cells express Vγ3/Vδ1. These cells, referred to as dendritic epidermal T cells (DETC) originate from fetal Vγ3+ thymocytes. The role of γδ TCR specificity in DETC's migration/localization to the skin has remained controversial. To address this issue we have generated transgenic (Tg) mice expressing a TCR δ chain (Vδ6.3-Dδ1-Dδ2-Jδ1-Cδ), which can pair with Vγ3 in fetal thymocytes but is not normally expressed by DETC. In wild-type (wt) Vδ6.3Tg mice DETC were present and virtually all of them express Vδ6.3. However, DETC were absent in TCR-δ−/− Vδ6.3Tg mice, despite the fact that Vδ6.3Tg γδ T cells were present in normal numbers in other lymphoid and nonlymphoid tissues. In wt Vδ6.3Tg mice, a high proportion of in-frame Vδ1 transcripts were found in DETC, suggesting that the expression of an endogenous TCR-δ (most probably Vδ1) was required for the development of Vδ6.3+ epidermal γδ T cells. Collectively our data demonstrate that TCR specificity is essential for the development of γδ T cells in the epidermis. Moreover, they show that the TCR-δ locus is not allelically excluded.

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