scholarly journals Reduced Frequency of Memory T Cells and Increased Th17 Responses in Patients with Active Tuberculosis

2012 ◽  
Vol 19 (10) ◽  
pp. 1667-1676 ◽  
Author(s):  
Nancy D. Marín ◽  
Sara C. París ◽  
Mauricio Rojas ◽  
Luis F. García
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Active Tuberculosis ◽  
T Cell Subsets ◽  
Phenotypic Characterization ◽  
Interleukin 17 ◽  
Content Type ◽  
Reduced Frequency ◽  
Latently Infected ◽  
Ifn Γ

ABSTRACTPhenotypic and functional alterations inMycobacterium tuberculosisT cell subsets have been reported in patients with active tuberculosis. A better understanding of these alterations will increase the knowledge about immunopathogenesis and also may contribute to the development of new diagnostics and prophylactic strategies. Here, theex vivophenotype of CD4+and CD8+T cells and the frequency and phenotype of gamma interferon (IFN-γ)- and interleukin 17 (IL-17)-producing cells elicited in short-term and long-term cultures following CFP-10 and purified protein derivative (PPD) stimulation were determined in noninfected persons (non-TBi), latently infected persons (LTBi), and patients with active tuberculosis (ATB). Phenotypic characterization of T cells was done based on the expression of CD45RO and CD27. Results show that ATB had a reduced frequency of circulating CD4+CD45RO+CD27+T cells and an increased frequency of CD4+CD45RO−CD27+T cells. ATB also had a higher frequency of circulating IL-17-producing CD4+T cells than did LTBi after PPD stimulation, whereas LTBi had more IFN-γ-producing CD4+T cells than did non-TBi. The phenotype of IFN-γ-producing cells at 24 h differs from the phenotype of IL-17-producing cells with no differences between LTBi and ATB. At 144 h, IFN-γ- and IL-17-producing cells were mainly CD45RO+CD27+T cells and they were more frequent in ATB. These results suggest thatM. tuberculosisinfection induces alterations in T cells which interfere with an adequate specific immune response.

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 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 Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection

2015 ◽  
Vol 83 (5) ◽  
pp. 2118-2126 ◽  
Author(s):  
Truc Hoang ◽  
Else Marie Agger ◽  
Joseph P. Cassidy ◽  
Jan P. Christensen ◽  
Peter Andersen
Keyword(s):  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Cd4 T Cells ◽  
Protein Energy Malnutrition ◽  
T Cell Subsets ◽  
Content Type ◽  
Protein Energy ◽  
Tnf Α ◽  
Ifn Γ

Protein energy malnutrition (PEM) increases susceptibility to infectious diseases, including tuberculosis (TB), but it is not clear how PEM influences vaccine-promoted immunity to TB. We demonstrate that PEM during low-level steady-state TB infection in a mouse model results in rapid relapse ofMycobacterium tuberculosis, as well as increased pathology, in bothMycobacterium bovisBCG-vaccinated and unvaccinated animals. PEM did not change the overall numbers of CD4 T cells in BCG-vaccinated animals but resulted in an almost complete loss of antigen-specific cytokine production. Furthermore, there was a change in cytokine expression characterized by a gradual loss of multifunctional antigen-specific CD4 T cells and an increased proportion of effector cells expressing gamma interferon and tumor necrosis factor alpha (IFN-γ+TNF-α+and IFN-γ+cells). PEM duringM. tuberculosisinfection completely blocked the protection afforded by the H56-CAF01 subunit vaccine, and this was associated with a very substantial loss of the interleukin-2-positive memory CD4 T cells promoted by this vaccine. Similarly, PEM during the vaccination phase markedly reduced the H56-CAF01 vaccine response, influencing all cytokine-producing CD4 T cell subsets, with the exception of CD4 T cells positive for TNF-α only. Importantly, this impairment was reversible and resupplementation of protein during infection rescued both the vaccine-promoted T cell response and the protective effect of the vaccine againstM. tuberculosisinfection.

scholarly journals Vaccinated C57BL/6 Mice Develop Protective and Memory T Cell Responses to Coccidioides posadasii Infection in the Absence of Interleukin-10

2013 ◽  
Vol 82 (2) ◽  
pp. 903-913 ◽  
Author(s):  
Chiung-Yu Hung ◽  
Natalia Castro-Lopez ◽  
Garry T. Cole
Keyword(s):  
T Cells ◽  
T Cell ◽  
Ex Vivo ◽  
Interleukin 10 ◽  
Effector Memory ◽  
Wild Type ◽  
Coccidioides Posadasii ◽  
Content Type ◽  
Cell Immunity ◽  
Ifn Γ

ABSTRACTHigh concentrations of lung tissue-associated interleukin-10 (IL-10), an anti-inflammatory and immunosuppressive cytokine, correlate with susceptibility of mice toCoccidioidesspp. infection. In this study, we found that macrophages, dendritic cells, neutrophils, and both CD8+and CD4+T cells recruited toCoccidioides posadasii-infected lungs of nonvaccinated and vaccinated mice contributed to the production of IL-10. The major IL-10-producing leukocytes were CD8+T cells, neutrophils, and macrophages in lungs of nonvaccinated mice, while both Foxp3+and Foxp3−subsets of IL-10+CD4+T cells were significantly elevated in vaccinated mice. Profiles of the recruited leukocytes in lungs revealed that only CD4+T cells were significantly increased inIL-10−/−knockout mice compared to their wild-type counterparts. Furthermore,ex vivorecall assays showed that CD4+T cells isolated from vaccinatedIL-10−/−mice compared to vaccinated wild-type mice produced significantly higher amounts of IL-2, gamma interferon (IFN-γ), IL-4, IL-6, and IL-17A in the presence of a coccidioidal antigen, indicating that IL-10 suppresses Th1, Th2, and Th17 immunity toCoccidioidesinfection. Analysis of absolute numbers of CD44+CD62L−CD4+T effector memory T cells (TEM) and IFN-γ- and IL-17A-producing CD4+T cells in the lungs ofCoccidioides-infected mice correlated with better fungal clearance in nonvaccinatedIL-10−/−mice than in nonvaccinated wild-type mice. Our results suggest that IL-10 suppresses CD4+T-cell immunity in nonvaccinated mice duringCoccidioidesinfection but does not impede the development of a memory response nor exacerbate immunopathology of vaccinated mice over at least a 4-month period after the last immunization.

scholarly journals Secretory Microneme Proteins Induce T-Cell Recall Responses in Mice Chronically Infected withToxoplasma gondii

mSphere ◽  
2019 ◽  
Vol 4 (1) ◽  
Author(s):  
Iti Saraav ◽  
Qiuling Wang ◽  
Kevin M. Brown ◽  
L. David Sibley
Keyword(s):  
T Cells ◽  
Immune Status ◽  
Memory T Cells ◽  
High Sensitivity ◽  
Host Cells ◽  
Antibody Detection ◽  
Effector Memory ◽  
Phenotypic Characterization ◽  
Content Type ◽  
Ifn Γ

ABSTRACTMicroneme (MIC) proteins play important roles in the recognition, adhesion, and invasion of host cells byToxoplasma gondii. Previous studies have shown that MIC proteins are highly immunogenic in the mouse and recognized by human serum antibodies. Here we report thatT. gondiiantigens MIC1, MIC3, MIC4, and MIC6 were capable of inducing memory responses leading to production of gamma interferon (IFN-γ) by T cells fromT. gondii-infected mice. Production of IFN-γ was demonstrated using enzyme-linked immunosorbent spot (ELISPOT) assay and also intracellular cytokine staining. All four MIC antigens displayed very high sensitivity (100%) and specificity (86 to 100%) for detecting chronic infection. Interestingly, IFN-γ was produced by both CD4+and CD8+T cells in BALB/c mice but primarily by CD4+T cells in C57BL/6 mice. Phenotypic characterization of IFN-γ-producing CD4+and CD8+T cells in BALB/c mice and CD4+T cells in C57BL/6 mice revealed effector memory T cells (CD44hiCD62Llo) as the predominant cells that contributed to IFN-γ production in response to MIC antigens. Effector memory responses were seen in mice of different major histocompatibility complex class II (MHC-II) haplotypes, suggesting that MIC antigens contain epitopes that are broadly recognized.IMPORTANCECurrent diagnosis of toxoplasmosis relies almost exclusively on antibody detection, and while detection of IgG provides a useful estimate of prior infection, it does not alone indicate immune status. In contrast, detection of IFN-γ responses toT. gondiiantigens has been used to monitor immune responsiveness in HIV-infected patients, thus providing valuable predictions about the potential for disease reactivation. However, specificT. gondiiantigens that can be used in assays to detect cellular immunity remain largely undefined. In this study, we examined the diagnostic potential of microneme antigens ofT. gondiiusing IFN-γ detection assays. Our findings demonstrate that MIC antigens (MIC1, MIC3, MIC4, and MIC6) elicit IFN-γ responses from memory T cells in chronically infected mice. Monitoring IFN-γ production by T cells stimulated with MIC antigens provided high sensitivity and specificity for detection ofT. gondiiinfection in mice. Taken together, these studies suggest that microneme antigens might be useful as an adjunct to serological testing to monitor immune status during infection.

scholarly journals Brief Ex Vivo Incubation with Fas Ligand Selectively Depletes Alloreactive T Cells and Antigen Presenting Cells from Stem Cell Grafts

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2033-2033
Author(s):  
Hilit Levy-Barazany ◽  
Liat Pinkas ◽  
Galina Rodionov ◽  
Nitzan Marelly ◽  
Michal Tzadok ◽  
...  
Keyword(s):  
T Cells ◽  
Stem Cell ◽  
T Cell ◽  
Fas Ligand ◽  
Ex Vivo ◽  
T Cell Subsets ◽  
Ifn Γ ◽  
Antigen Presenting

Abstract Graft versus host disease (GvHD) proceeds to be the Achilles' heel of hematopoietic stem cell transplantation, with clinicians continue facing a classic conflict: too much GvHD and the patient is at risk for transplant-related mortality and decreased quality of life; too little GvHD and the patient is at increased risk of relapse of their malignant disease. T cells and antigen presenting cells (APCs) are major components of the hematopoietic G-CSF mobilized peripheral blood cells (PBCs) graft. While GvHD is T cell mediated, the APCs are required for the initiation and maintenance of the GvHD. To reduce the risk for GvHD, grafts are sometimes depleted of their T cells, however, while preventing GvHD, the critically important attributes of graft versus leukemia (GvL) effect and engraftment are reduced significantly. Novel strategies that aim to abrogate or ameliorate GvHD, while preserving engraftment and GvL are of great need. A short incubation (2hr) of G-CSF mobilized PBCs with multimeric Fas ligand (i.e. ApoGraft) selectively induces apoptosis in T cell subsets and APCs (Panels A and B), but not in CD34+ progenitor cells (data not shown). FasL treatment preferentially induces apoptosis in mature T cell subsets which express high levels of Fas (CD95), such as T stem cell memory (TSCM), T central memory (TCM), and T effector memory (TEM) cells, as well as the pro-inflammatory T cell subtypes TH1 and TH17 cells, while no apoptotic signal is detected in the non-expressing CD95 naïve T cells (Panel A). The expression of T cells and APCs activation markers; CD25 and HLA-DR, respectively, is significantly reduced following apoptotic challenge in vitro (Panel C), as well as in transplanted mice (data not shown). Furthermore, upon an activation stimulus with anti CD3/CD28 beads in vitro, ApoGraft derived T cells secrete lower levels of IFN-γ, than G-CSF mobilized PBCs derived T cells (Panel D). To gain deeper understanding of the kinetics of GvHD development in vivo, NSG mice were transplanted with ApoGraft or G-CSF mobilized PBCs. Homing, expansion and differentiation of human leukocytes subtypes within the mice bone marrow, spleen and blood, were monitored 3, 7 and 14 days post transplantation. Decreased levels of T and B cells infiltration and expansion were detected in the spleen (Panels E and F), suggesting reduced formation of allo-reactive T cell clones. Reduced proliferation of these cells was associated with lower levels of IFN-γ secreted to the plasma (Panel H) and was in correlation with reduced GvHD and prolonged survival of the ApoGraft transplanted mice (Panel G). Importantly, we have previously demonstrated both in-vitro and in-vivo that ApoGraft has similar GvL and stem cell engraftment capabilities, compared to control G-CSF mobilized PBCs (data not shown). In conclusion, in contrast to conventional T- cell depletion methods, ApoGraft, an ex-vivo FasL-treated graft, affects both the T-cells and APCs, leading to reduced GvHD, while maintaining GvL and engraftment potential (Panel I). ApoGraft is currently being evaluated in a Phase I/II clinical trial (NCT02828878) in subjects with hematologic malignancies undergoing matched related allo-HSCT. Figure. Figure. Disclosures Levy-Barazany: Cellect Biotherapeutics Ltd: Employment. Pinkas:Cellect Biotherapeutics Ltd: Employment. Rodionov:Cellect Biotherapeutics Ltd: Employment. Marelly:Cellect Biotherapeutics Ltd: Employment. Tzadok:Cellect Biotherapeutics Ltd: Employment. Bakimer:Cellect Biotherapeutics Ltd: Employment. Yarkoni:Cellect Biotherapeutics Ltd: Employment. Peled:Cellect Biotherapeutics Ltd: Consultancy. Zuckerman:Cellect Biotherapeutics Ltd: Consultancy.

scholarly journals Mixed Formulation of Conventional and Pegylated Meglumine Antimoniate-Containing Liposomes Reduces Inflammatory Process and Parasite Burden in Leishmania infantum-Infected BALB/c Mice

2017 ◽  
Vol 61 (11) ◽  
Author(s):  
Levi Eduardo Soares Reis ◽  
Rory Cristiane Fortes de Brito ◽  
Jamille Mirelle de Oliveira Cardoso ◽  
Fernando Augusto Siqueira Mathias ◽  
Rodrigo Dian Oliveira Aguiar Soares ◽  
...  
Keyword(s):  
T Cells ◽  
Leishmania Infantum ◽  
Inflammatory Process ◽  
Parasite Burden ◽  
T Cell Subsets ◽  
Content Type ◽  
Meglumine Antimoniate ◽  
First Choice ◽  
Ifn Γ

ABSTRACT Pentavalent antimonial has been the first choice treatment for visceral leishmaniasis; however, it has several side effects that leads to low adherence to treatment. Liposome-encapsulated meglumine antimoniate (MA) arises as an important strategy for chemotherapy enhancement. We evaluated the immunopathological changes using the mixture of conventional and pegylated liposomes with MA. The mice were infected with Leishmania infantum and a single-dose treatment regimen. Comparison was made with groups treated with saline, empty liposomes, free MA, and a liposomal formulation of MA (Lipo MA). Histopathological analyses demonstrated that animals treated with Lipo MA showed a significant decrease in the inflammatory process and the absence of granulomas. The in vitro stimulation of splenocytes showed a significant increase of gamma interferon (IFN-γ) produced by CD8+ T cells and a decrease in interleukin-10 (IL-10) produced by CD4+ and CD8+ T cells in the Lipo MA. Furthermore, the Lipo MA group showed an increase in the IFN-γ/IL-10 ratio in both CD4+ and CD8+ T cell subsets. According to the parasite load evaluation using quantitative PCR, the Lipo MA group showed no L. infantum DNA in the spleen (0.0%) and 41.4% in the liver. In addition, we detected a low positive correlation between parasitism and histopathology findings (inflammatory process and granuloma formation). Thus, our results confirmed that Lipo MA is a promising antileishmanial formulation able to reduce the inflammatory response and induce a type 1 immune response, accompanied by a significant reduction of the parasite burden into hepatic and splenic compartments in treated animals.

scholarly journals The Dual Role of the β2-Adrenoreceptor in the Modulation of IL-17 and IFN-γ Production by T Cells in Multiple Sclerosis

2022 ◽  
Vol 23 (2) ◽  
pp. 668
Author(s):  
Mikhail Melnikov ◽  
Vladimir Rogovskii ◽  
Anastasiya Sviridova ◽  
Anna Lopatina ◽  
Mikhail Pashenkov ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
T Cells ◽  
Cd4 T Cells ◽  
Cytokine Production ◽  
Ex Vivo ◽  
Inhibitory Effect ◽  
Interferon Γ ◽  
Interleukin 17 ◽  
Ifn Γ

Norepinephrine is a neurotransmitter that also has an immunomodulatory effect and is involved in multiple sclerosis (MS) pathogenesis. This study aimed to clarify the role of the β2-adrenoreceptor in the norepinephrine-mediated modulation of interleukin-17 (IL-17) and interferon-γ (IFN-γ) production, which play a critical pathogenetic role in MS. CD4+ T cells obtained from twenty-five relapsing-remitting MS patients and sixteen healthy subjects were cultured ex vivo with norepinephrine and/or β2-adrenoreceptor antagonist or agonist, followed by a cytokine production analysis using ELISA. Norepinephrine suppressed IL-17 and IFN-γ production by the anti-CD3/anti-CD28-microbead-stimulated CD4+ T cells in both groups. Blockade of the β2-adrenoreceptor with the specific antagonist ICI 118.551 enhanced norepinephrine-mediated IL-17 suppression but decreased its inhibitory effect on IFN-γ production in MS patients. In contrast, the β2-adrenoreceptor agonist formoterol did not influence norepinephrine’s inhibitory effect on cytokine production in both groups. The blockade of the β2-adrenoreceptor, even in the absence of exogenous norepinephrine, suppressed IL-17 production but did not influence IFN-γ production in both groups. Conversely, β2-adrenoreceptor activation by formoterol decreased IFN-γ production and did not affect IL-17 production in both groups. These data illustrate the inhibitory effect of norepinephrine on IL-17 and IFN-γ production by CD4+ T cells in MS. The inhibitory effect of norepinephrine on IFN-γ production by CD4+ T cells in MS could be mediated via β2-adrenoreceptor activation.

scholarly journals Ex Vivo Kinetics of Early and Long-Term Multifunctional Human Leukocyte Antigen E-Specific CD8+ Cells in Volunteers Immunized with the Ty21a Typhoid Vaccine

2010 ◽  
Vol 17 (9) ◽  
pp. 1305-1314 ◽  
Author(s):  
Rosângela Salerno-Goncalves ◽  
Rezwanul Wahid ◽  
Marcelo B. Sztein
Keyword(s):  
T Cells ◽  
Ex Vivo ◽  
Interleukin 2 ◽  
T Cell Subsets ◽  
Effector Memory ◽  
Typhoid Vaccine ◽  
Tnf Α ◽  
Ifn Γ ◽  
Kinetics Of

ABSTRACT T cells are likely to play an important role in the host defense against Salmonella enterica serovar Typhi, the causative agent of typhoid fever. We have shown that HLA-E can function as a restriction element for S. Typhi-specific CD8+ T cells. Because of the potential importance of HLA-E-restricted CD8+ responses in resistance to Salmonella infection, we characterized these responses and investigated their kinetics of appearance and persistence in volunteers immunized orally with the licensed attenuated Ty21a strain typhoid vaccine. Cells were obtained from volunteers before and at days 2, 4, 7, 10, 14, 28, 42, 56, 120, 180, 360, and 720 after immunization. An ex vivo multicolor staining panel including antibodies to CD107a and -b, interleukin-2, gamma interferon (IFN-γ), and tumor necrosis factor alpha (TNF-α) was used to functionally assess memory T-cell subsets by flow cytometry. Increases in cytokine-secreting CD8+ cells were observed in the T effector/memory (TEM) and CD45RA+ TEM (TEMRA) subsets as early as 4 days after immunization and persisted, particularly in the TEMRA subset, up to 2 years after immunization. The majority of HLA-E-restricted CD8+ cells 28 to 56 days after immunization coexpressed CD107, IFN-γ, and TNF-α, showing characteristic features of multifunctional T cells. In summary, the multifunctionality and longevity of the HLA-E-restricted CD8 responses observed in this study highlight their significance in adaptive immunity to S. Typhi. Finally, this is the first demonstration, in either animals or humans, of the presence of long-term multifunctional HLA-E-restricted CD8+ cells after immunization.

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