scholarly journals γδ-T cells promote IFN-γ–dependent Plasmodium pathogenesis upon liver-stage infection

2019 ◽  
Vol 116 (20) ◽  
pp. 9979-9988 ◽  
Author(s):  
Julie C. Ribot ◽  
Rita Neres ◽  
Vanessa Zuzarte-Luís ◽  
Anita Q. Gomes ◽  
Liliana Mancio-Silva ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cerebral Malaria ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Γδ T Cells ◽  
Experimental Cerebral Malaria ◽  
Liver Stage ◽  
Ifn Γ ◽  
Stage Infection

Cerebral malaria (CM) is a major cause of death due to Plasmodium infection. Both parasite and host factors contribute to the onset of CM, but the precise cellular and molecular mechanisms that contribute to its pathogenesis remain poorly characterized. Unlike conventional αβ-T cells, previous studies on murine γδ-T cells failed to identify a nonredundant role for this T cell subset in experimental cerebral malaria (ECM). Here we show that mice lacking γδ-T cells are resistant to ECM when infected with Plasmodium berghei ANKA sporozoites, the liver-infective form of the parasite and the natural route of infection, in contrast with their susceptible phenotype if challenged with P. berghei ANKA-infected red blood cells that bypass the liver stage of infection. Strikingly, the presence of γδ-T cells enhanced the expression of Plasmodium immunogenic factors and exacerbated subsequent systemic and brain-infiltrating inflammatory αβ-T cell responses. These phenomena were dependent on the proinflammatory cytokine IFN-γ, which was required during liver stage for modulation of the parasite transcriptome, as well as for downstream immune-mediated pathology. Our work reveals an unanticipated critical role of γδ-T cells in the development of ECM upon Plasmodium liver-stage infection.

scholarly journals IFN-γ–Producing CD4+ T Cells Promote Experimental Cerebral Malaria by Modulating CD8+ T Cell Accumulation within the Brain

2012 ◽  
Vol 189 (2) ◽  
pp. 968-979 ◽  
Author(s):  
Ana Villegas-Mendez ◽  
Rachel Greig ◽  
Tovah N. Shaw ◽  
J. Brian de Souza ◽  
Emily Gwyer Findlay ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cerebral Malaria ◽  
Cd4 T Cells ◽  
Cd8 T Cell ◽  
Experimental Cerebral Malaria ◽  
Cell Accumulation ◽  
Ifn Γ ◽  
The Brain

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.

Nitric oxide plays a critical role in suppression of T-cell proliferation by mesenchymal stem cells

Blood ◽  
2006 ◽  
Vol 109 (1) ◽  
pp. 228-234 ◽  
Author(s):  
Kazuya Sato ◽  
Katsutoshi Ozaki ◽  
Iekuni Oh ◽  
Akiko Meguro ◽  
Keiko Hatanaka ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Stem Cells ◽  
Cell Proliferation ◽  
T Cells ◽  
Mesenchymal Stem Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Specific Inhibitor ◽  
T Cell Proliferation

Abstract The molecular mechanisms by which mesenchymal stem cells (MSCs) suppress T-cell proliferation are poorly understood, and whether a soluble factor plays a major role remains controversial. Here we demonstrate that the T-cell–receptor complex is not a target for the suppression, suggesting that downstream signals mediate the suppression. We found that Stat5 phosphorylation in T cells is suppressed in the presence of MSCs and that nitric oxide (NO) is involved in the suppression of Stat5 phosphorylation and T-cell proliferation. The induction of inducible NO synthase (NOS) was readily detected in MSCs but not T cells, and a specific inhibitor of NOS reversed the suppression of Stat5 phosphorylation and T-cell proliferation. This production of NO in the presence of MSCs was mediated by CD4 or CD8 T cells but not by CD19 B cells. Furthermore, inhibitors of prostaglandin synthase or NOS restored the proliferation of T cells, whereas an inhibitor of indoleamine 2,3-dioxygenase and a transforming growth factor–β–neutralizing antibody had no effect. Finally, MSCs from inducible NOS−/− mice had a reduced ability to suppress T-cell proliferation. Taken together, these results suggest that NO produced by MSCs is one of the major mediators of T-cell suppression by MSCs.

scholarly journals Splicing factor SRSF1 limits IFN-γ production via RhoH and ameliorates experimental nephritis

Rheumatology ◽  
2020 ◽  
Vol 60 (1) ◽  
pp. 420-429
Author(s):  
Takayuki Katsuyama ◽  
Hao Li ◽  
Suzanne M Krishfield ◽  
Vasileios C Kyttaris ◽  
Vaishali R Moulton
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Elevated Serum ◽  
Splicing Factor ◽  
Type I ◽  
Human T Cells ◽  
Experimental Nephritis ◽  
Ifn Γ

Abstract Objective CD4 T helper 1 (Th1) cells producing IFN-γ contribute to inflammatory responses in the pathogenesis of SLE and lupus nephritis. Moreover, elevated serum type II IFN levels precede the appearance of type I IFNs and autoantibodies in patient years before clinical diagnosis. However, the molecules and mechanisms that control this inflammatory response in SLE remain unclear. Serine/arginine-rich splicing factor 1 (SRSF1) is decreased in T cells from SLE patients, and restrains T cell hyperactivity and systemic autoimmunity. Our objective here was to evaluate the role of SRSF1 in IFN-γ production, Th1 differentiation and experimental nephritis. Methods T cell-conditional Srsf1-knockout mice were used to study nephrotoxic serum-induced nephritis and evaluate IFN-γ production and Th1 differentiation by flow cytometry. RNA sequencing was used to assess transcriptomics profiles. RhoH was silenced by siRNA transfections in human T cells by electroporation. RhoH and SRSF1 protein levels were assessed by immunoblots. Results Deletion of Srsf1 in T cells led to increased Th1 differentiation and exacerbated nephrotoxic serum nephritis. The expression levels of RhoH are decreased in Srsf1-deficient T cells, and silencing RhoH in human T cells leads to increased production of IFN-γ. Furthermore, RhoH expression was decreased and directly correlated with SRSF1 in T cells from SLE patients. Conclusion Our study uncovers a previously unrecognized role of SRSF1 in restraining IFN-γ production and Th1 differentiation through the control of RhoH. Reduced expression of SRSF1 may contribute to pathogenesis of autoimmune-related nephritis through these molecular mechanisms.

scholarly journals Critical Role for SLAM/SAP Signaling in the Thymic Developmental Programming of IL-17– and IFN-γ–Producing γδ T Cells

2020 ◽  
Vol 204 (6) ◽  
pp. 1521-1534 ◽  
Author(s):  
Oliver Dienz ◽  
Victoria L. DeVault ◽  
Shawn C. Musial ◽  
Somen K. Mistri ◽  
Linda Mei ◽  
...  
Keyword(s):  
T Cells ◽  
Critical Role ◽  
Γδ T Cells ◽  
Developmental Programming ◽  
Ifn Γ

Ligation of CD137 receptor prevents and reverses established anergy of CD8+ cytolytic T lymphocytes in vivo

Blood ◽  
2004 ◽  
Vol 103 (1) ◽  
pp. 177-184 ◽  
Author(s):  
Ryan A. Wilcox ◽  
Koji Tamada ◽  
Dallas B. Flies ◽  
Gefeng Zhu ◽  
Andrei I. Chapoval ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Molecular Mechanisms ◽  
Transplant Rejection ◽  
Critical Role ◽  
Tumor Necrosis Factor Receptor ◽  
T Cell Anergy ◽  
Cell Anergy ◽  
Induced Tolerance

Abstract T-cell anergy is a tolerance mechanism defined as a hyporesponsive status of antigen-specific T cells upon prior antigen encounter and is believed to play a critical role in the evasion of tumor immunity and the amelioration of allogeneic transplant rejection. Molecular mechanisms in controlling T-cell anergy are less known. We show here that administration of an agonistic monoclonal antibody (mAb) to CD137, a member of the tumor necrosis factor receptor superfamily, prevents the induction of CD8+ cytolytic T-lymphocyte (CTL) anergy by soluble antigens. More importantly, CD137 mAb restores the functions of established anergic CTLs upon reencountering their cognate antigen. As a result, infusion of CD137 mAb inhibits progressive tumor growth that is caused by soluble tumor antigen-induced tolerance in a P815R model. CD137 mAb also restores proliferation and effector functions of anergic alloreactive 2C T cells in a bone marrow transplantation model. Our results indicate that ligation of CD137 receptor delivers a regulatory signal for T-cell anergy and implicate manipulation of the CD137 pathway as a new approach to break T-cell tolerance.

scholarly journals Effector CD8+ T Lymphocytes against Liver Stages of Plasmodium yoelii Do Not Require Gamma Interferon for Antiparasite Activity

2008 ◽  
Vol 76 (8) ◽  
pp. 3628-3631 ◽  
Author(s):  
Sumana Chakravarty ◽  
G. Christian Baldeviano ◽  
Michael G. Overstreet ◽  
Fidel Zavala
Keyword(s):  
T Cells ◽  
T Cell ◽  
Protective Immunity ◽  
Critical Role ◽  
Plasmodium Yoelii ◽  
Gamma Interferon ◽  
Parasite Development ◽  
Wild Type ◽  
Ifn Γ

ABSTRACT The protective immune response against liver stages of the malaria parasite critically requires CD8+ T cells. Although the nature of the effector mechanism utilized by these cells to repress parasite development remains unclear, a critical role for gamma interferon (IFN-γ) has been widely assumed based on circumstantial evidence. However, the requirement for CD8+ T-cell-mediated IFN-γ production in protective immunity to this pathogen has not been directly tested. In this report, we use an adoptive transfer strategy with circumsporozoite (CS) protein-specific transgenic T cells to examine the role of CD8+ T-cell-derived IFN-γ production in Plasmodium yoelii-infected mice. We show that despite a marginal reduction in the expansion of naive IFN-γ-deficient CS-specific transgenic T cells, their antiparasite activity remains intact. Further, adoptively transferred IFN-γ-deficient CD8+ T cells were as efficient as their wild-type counterparts in limiting parasite growth in naive mice. Taken together, these studies demonstrate that IFN-γ secretion by CS-specific CD8+ T cells is not essential to protect mice against live sporozoite challenge.

scholarly journals Critical role of host γδ T cells in experimental acute graft-versus-host disease

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 749-755 ◽  
Author(s):  
Yoshinobu Maeda ◽  
Pavan Reddy ◽  
Kathleen P. Lowler ◽  
Chen Liu ◽  
Dennis Keith Bishop ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Graft Versus Host Disease ◽  
Critical Role ◽  
Γδ T Cells ◽  
Allogeneic Bone ◽  
Host Disease ◽  
Graft Versus Host ◽  
Tnf Α

Abstract γδ T cells localize to target tissues of graft-versus-host disease (GVHD) and therefore we investigated the role of host γδ T cells in the pathogenesis of acute GVHD in several well-characterized allogeneic bone marrow transplantation (BMT) models. Depletion of host γδ T cells in wild-type (wt) B6 recipients by administration of anti-T-cell receptor (TCR) γδ monoclonal antibody reduced GVHD, and γδ T-cell-deficient (γδ-/-) BM transplant recipients experienced markedly improved survival compared with normal controls (63% vs 10%, P < .001). γδ T cells were responsible for this difference because reconstitution of γδ-/- recipients with γδ T cells restored GVHD mortality. γδ-/- recipients showed decreased serum levels of tumor necrosis factor α (TNF-α), less GVHD histopathologic damage, and reduced donor T-cell expansion. Mechanistic analysis of this phenomenon demonstrated that dendritic cells (DCs) from γδ-/- recipients exhibited less allostimulatory capacity compared to wt DCs after irradiation. Normal DCs derived from BM caused greater allogeneic T-cell proliferation when cocultured with γδ T cells than DCs cocultured with medium alone. This enhancement did not depend on interferon γ (IFN-γ), TNF-α, or CD40 ligand but did depend on cell-to-cell contact. These data demonstrated that the host γδ T cells exacerbate GVHD by enhancing the allostimulatory capacity of host antigen-presenting cells. (Blood. 2005;106:749-755)

scholarly journals Early Induction of Interleukin-10 Limits Antigen-Specific CD4+T Cell Expansion, Function, and Secondary Recall Responses during Persistent Phagosomal Infection

2014 ◽  
Vol 82 (10) ◽  
pp. 4092-4103 ◽  
Author(s):  
Abinav Kumar Singh ◽  
Nagaraja R. Thirumalapura
Keyword(s):  
T Cells ◽  
T Cell ◽  
Functional Status ◽  
Persistent Infection ◽  
Inflammatory Responses ◽  
Critical Role ◽  
Interleukin 10 ◽  
Host Cells ◽  
Content Type ◽  
Ifn Γ

ABSTRACTDiverse pathogens have evolved to survive and replicate in the endosomes or phagosomes of the host cells and establish persistent infection. Ehrlichiae are Gram-negative, intracellular bacteria that are transmitted by ticks. Ehrlichiae reside in the endosomes of the host phagocytic or endothelial cells and establish persistent infection in their vertebrate reservoir hosts. CD4+T cells play a critical role in protection against phagosomal infections. In the present study, we investigated the expansion, maintenance, and functional status of antigen-specific CD4+T cells during persistentEhrlichia murisinfection in wild-type and interleukin-10 (IL-10)-deficient mice. Our study indicated that early induction of IL-10 led to reduced inflammatory responses and impaired bacterial clearance during persistentEhrlichiainfection. Notably, we demonstrated that the functional production of gamma interferon (IFN-γ) by antigen-specific CD4+T cells maintained during a persistent phagosomal infection progressively deteriorates. The functional loss of IFN-γ production by antigen-specific CD4+T cells was reversed in the absence of IL-10. Furthermore, we demonstrated that transient blockade of IL-10 receptor during the T cell priming phase early in infection was sufficient to enhance the magnitude and the functional capacity of antigen-specific effector and memory CD4+T cells, which translated into an enhanced recall response. Our findings provide new insights into the functional status of antigen-specific CD4+T cells maintained during persistent phagosomal infection. The study supports the concept that a better understanding of the factors that influence the priming and differentiation of CD4+T cells may provide a basis to induce a protective immune response against persistent infections.

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