scholarly journals A proportion of CD4+ T cells from patients with chronic Chagas disease undergo a dysfunctional process, which is partially reversed by benznidazole treatment

2021 ◽  
Vol 15 (2) ◽  
pp. e0009059
Author(s):  
Elena Pérez-Antón ◽  
Adriana Egui ◽  
M. Carmen Thomas ◽  
Bartolomé Carrilero ◽  
Marina Simón ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chagas Disease ◽  
Granzyme B ◽  
Cell Subset ◽  
Inhibitory Receptors ◽  
Cardiac Symptoms ◽  
Before And After ◽  
Ifn Γ ◽  
Chronic Chagas Disease

Background Signs of senescence and the late stages of differentiation associated with the more severe forms of Chagas disease have been described in the Trypanosoma cruzi antigen-specific CD4+ T-cell population. However, the mechanisms involved in these functions are not fully known. To date, little is known about the possible impact of benznidazole treatment on the T. cruzi-specific functional response of CD4+ T cells. Methodology/Principal findings The functional capacity of CD4+ T cells was analyzed by cytometric assays in chronic Chagas disease patients, with indeterminate form (IND) and cardiac alterations (CCC) (25 and 15, respectively) before and after benznidazole treatment. An increase in the multifunctional capacity (expression of IFN-γ, IL-2, TNF-α, perforin and/or granzyme B) of the antigen-specific CD4+ T cells was observed in indeterminate versus cardiac patients, which was associated with the reduced coexpression of inhibitory receptors (2B4, CD160, CTLA-4, PD-1 and/or TIM-3). The functional profile of these cells shows statistically significant differences between IND and CCC (p<0.001), with a higher proportion of CD4+ T cells coexpressing 2 and 3 molecules in IND (54.4% versus 23.1% and 4.1% versus 2.4%, respectively). A significant decrease in the frequencies of CD4+ T cells that coexpress 2, 3 and 4 inhibitory receptors was observed in IND after 24–48 months of treatment (p<0.05, p<0.01 and p<0.05, respectively), which was associated with an increase in antigen-specific multifunctional activity. The IND group showed, at 9–12 months after treatment, an increase in the CD4+ T cell subset coproducing three molecules, which were mainly granzyme B+, perforin+ and IFN-γ+ (1.4% versus 4.5%). Conclusions/Significance A CD4+ T cell dysfunctional process was detected in chronic Chagas disease patients, being more exacerbated in those patients with cardiac symptoms. After short-term benznidazole treatment (9–12 months), indeterminate patients showed a significant increase in the frequency of multifunctional antigen-specific CD4+ T cells.

HCA587 protein vaccine induces specific antitumor immunity mediated by CD4+ T-cells expressing granzyme B in a mouse model of melanoma

2020 ◽  
Vol 20 ◽  
Author(s):  
Weiming Yang ◽  
Weiheng Zhang ◽  
Xiaozhong Wang ◽  
Liming Tan ◽  
Hua Li ◽  
...  
Keyword(s):  
T Cells ◽  
Cd4 T Cells ◽  
Antitumor Effect ◽  
Granzyme B ◽  
Cell Subset ◽  
Cell Mediated Immunity ◽  
Protein Vaccine ◽  
Tumor Tissues ◽  
Wide Range ◽  
Ifn Γ

Background: The antigen HCA587 (also known as MAGE-C2), which is considered a cancer-testis antigen, exhibits upregulated expression in a wide range of malignant tumors with unique immunological properties, and may thus serve as a promising target for tumor immunotherapy. Objective: To explore the antitumor effect of the HCA587 protein vaccine and the response of humoral and cell-mediated immunity. Methods: The HCA587 protein vaccine was formulated with adjuvants CpG and and ISCOM. B16 melanoma cells were subcutaneously inoculated to C57BL/6 mice, followed by treatment with HCA587 protein vaccine subcutaneously. Mouse survival was monitored daily, and tumor volume was measured every 2 to 3 days. The tumor sizes, survival time and immune cells in tumor tissues were detected. And the vital immune cell subset and effector molecules were explored. Results: After treatment with HCA587 protein vaccine, the vaccination generated elicited significant immune responses, which delayed tumor growth and improved animal survival. The vaccination increased the proportion of CD4+ T cells expressing IFN-γ and granzyme B in tumor tissues. Depletion of CD4+T cells resulted in an almost complete abrogation of the antitumor effect of the vaccination, suggesting that the antitumor efficacy was mediated by CD4+ T cells. In addition, knockout of IFN-γ resulted in a decrease in granzyme B levels which were secreted by CD4+ T cells, and the antitumor effect was also significantly attenuated. Conclusion: The HCA587 protein vaccine may increase the levels of granzyme B expressed by CD4+ T cells, and this increase is dependent on IFN-γ, and the vaccine resulted in a specific tumor immune response and subsequent eradication of the tumor.

Activation of Peripheral Blood T Cells by Interaction and Migration Through Endothelium: Role of Lymphocyte Function Antigen-1/Intercellular Adhesion Molecule-1 and Interleukin-15

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 886-896 ◽  
Author(s):  
David Sancho ◽  
Marı́a Yáñez-Mó ◽  
Reyes Tejedor ◽  
Francisco Sánchez-Madrid
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Cell Subset ◽  
Intercellular Adhesion Molecule ◽  
Lymphocyte Function ◽  
Ifn Γ

Abstract Cell adhesion molecules have a key role in the migration of T cells to inflammatory foci. However, the effect of the endothelial-lymphocyte interaction on the activation of the latter cells remains unresolved. We have studied the effect of resting and stimulated endothelial cells (ECs) on the activation of peripheral blood T cells (PBTLs), as assessed by the expression of CD69 and CD25 activation antigens. The incubation of PBTLs with tumor necrosis factor-–activated EC monolayers, either alive or fixed, induced the expression of CD69 but not CD25, preferentially in the CD8+CD45RO+ cell subset. Furthermore, it induced the production of cytokines such as IFN-γ, but not that of interleukin-2 (IL-2) and IL-4. EC treated with other stimuli such as IL-1β, IFN-γ, or lipopolysaccharide also showed the same proactivatory effect on T cells. Lymphocyte activation was almost completely inhibited by blocking anti-CD18 and anti–intercellular adhesion molecule-1 (anti–ICAM-1) monoclonal antibodies (MoAbs), but only slightly affected by MoAbs against CD49d, vascular cell adhesion molecule-1, and anti–IL-15. In addition, the interaction of PBTL with immobilized ICAM-1 induced CD69 expression in the same memory T-cell subset. IL-15 induced T-cell activation with expression of CD69 and CD25, and production of IFN-γ, and its effect was additive with that triggered by cell adhesion to either EC or immobilized ICAM-1. The transmigration of PBTLs through either confluent EC monolayers or ICAM-1–coated membranes also induced efficiently the expression of CD69. When IL-15 was used as chemoattractant in these assays, a further enhancement in CD69 expression was observed in migrated cells. Together these results indicate that stimulated endothelium may have an important role in T-cell activation, through the lymphocyte function antigen-1/ICAM-1 pathway, and that IL-15 efficiently cooperates in this phenomenon. These observations could account for the abundance of CD69+ cells in the lymphocytic infiltrates of several chronic inflammatory diseases.

scholarly journals IL-1 enhances expansion, effector function, tissue localization, and memory response of antigen-specific CD8 T cells

2013 ◽  
Vol 210 (3) ◽  
pp. 491-502 ◽  
Author(s):  
Shlomo Z. Ben-Sasson ◽  
Alison Hogg ◽  
Jane Hu-Li ◽  
Paul Wingfield ◽  
Xi Chen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Granzyme B ◽  
Interleukin 1 ◽  
Cd8 T Cell ◽  
Cell Receptor ◽  
In Vivo Models ◽  
Ifn Γ

Here, we show that interleukin-1 (IL-1) enhances antigen-driven CD8 T cell responses. When administered to recipients of OT-I T cell receptor transgenic CD8 T cells specific for an ovalbumin (OVA) peptide, IL-1 results in an increase in the numbers of wild-type but not IL1R1−/− OT-I cells, particularly in spleen, liver, and lung, upon immunization with OVA and lipopolysaccharide. IL-1 administration also results in an enhancement in the frequency of antigen-specific cells that are granzyme B+, have cytotoxic activity, and/ or produce interferon γ (IFN-γ). Cells primed in the presence of IL-1 display enhanced expression of granzyme B and increased capacity to produce IFN-γ when rechallenged 2 mo after priming. In three in vivo models, IL-1 enhances the protective value of weak immunogens. Thus, IL-1 has a marked enhancing effect on antigen-specific CD8 T cell expansion, differentiation, migration to the periphery, and memory.

Activation of Peripheral Blood T Cells by Interaction and Migration Through Endothelium: Role of Lymphocyte Function Antigen-1/Intercellular Adhesion Molecule-1 and Interleukin-15

Blood ◽  
1999 ◽  
Vol 93 (3) ◽  
pp. 886-896 ◽  
Author(s):  
David Sancho ◽  
Marı́a Yáñez-Mó ◽  
Reyes Tejedor ◽  
Francisco Sánchez-Madrid
Keyword(s):  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
T Cell Activation ◽  
Adhesion Molecule ◽  
Cell Activation ◽  
Cell Subset ◽  
Intercellular Adhesion Molecule ◽  
Lymphocyte Function ◽  
Ifn Γ

Cell adhesion molecules have a key role in the migration of T cells to inflammatory foci. However, the effect of the endothelial-lymphocyte interaction on the activation of the latter cells remains unresolved. We have studied the effect of resting and stimulated endothelial cells (ECs) on the activation of peripheral blood T cells (PBTLs), as assessed by the expression of CD69 and CD25 activation antigens. The incubation of PBTLs with tumor necrosis factor-–activated EC monolayers, either alive or fixed, induced the expression of CD69 but not CD25, preferentially in the CD8+CD45RO+ cell subset. Furthermore, it induced the production of cytokines such as IFN-γ, but not that of interleukin-2 (IL-2) and IL-4. EC treated with other stimuli such as IL-1β, IFN-γ, or lipopolysaccharide also showed the same proactivatory effect on T cells. Lymphocyte activation was almost completely inhibited by blocking anti-CD18 and anti–intercellular adhesion molecule-1 (anti–ICAM-1) monoclonal antibodies (MoAbs), but only slightly affected by MoAbs against CD49d, vascular cell adhesion molecule-1, and anti–IL-15. In addition, the interaction of PBTL with immobilized ICAM-1 induced CD69 expression in the same memory T-cell subset. IL-15 induced T-cell activation with expression of CD69 and CD25, and production of IFN-γ, and its effect was additive with that triggered by cell adhesion to either EC or immobilized ICAM-1. The transmigration of PBTLs through either confluent EC monolayers or ICAM-1–coated membranes also induced efficiently the expression of CD69. When IL-15 was used as chemoattractant in these assays, a further enhancement in CD69 expression was observed in migrated cells. Together these results indicate that stimulated endothelium may have an important role in T-cell activation, through the lymphocyte function antigen-1/ICAM-1 pathway, and that IL-15 efficiently cooperates in this phenomenon. These observations could account for the abundance of CD69+ cells in the lymphocytic infiltrates of several chronic inflammatory diseases.

scholarly journals Rapid Development of a Gamma Interferon-Secreting Glycolipid/CD1d-Specific Vα14+ NK1.1− T-Cell Subset after Bacterial Infection

2006 ◽  
Vol 74 (10) ◽  
pp. 5903-5913 ◽  
Author(s):  
Masashi Emoto ◽  
Izumi Yoshizawa ◽  
Yoshiko Emoto ◽  
Mamiko Miamoto ◽  
Robert Hurwitz ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Bacterial Infection ◽  
Rapid Development ◽  
Cell Subset ◽  
Gamma Interferon ◽  
Interleukin 12 ◽  
T Cell Subset ◽  
Early Stages ◽  
Ifn Γ

ABSTRACT The phenotypic and functional changes of glycolipid presented by CD1d(glycolipid/CD1d) specific Vα14+ T cells in the liver of mice at early stages of bacterial infection were investigated. After Listeria monocytogenes infection or interleukin-12 (IL-12) treatment, α-galactosylceramide/CD1d tetramer-reactive (α-GalCer/CD1d+) T cells coexpressing natural killer (NK) 1.1 marker became undetectable and, concomitantly, cells lacking NK1.1 emerged in both euthymic and thymectomized animals. Depletion of the NK1.1+ subpopulation prevented the emergence of α-GalCer/CD1d+ NK1.1− T cells. Before infection, NK1.1+, rather than NK1.1−, α-GalCer/CD1d+ T cells coexpressing CD4 were responsible for IL-4 production, whereas gamma interferon (IFN-γ) was produced by cells regardless of NK1.1 or CD4 expression. After infection, IL-4-secreting cells became undetectable among α-GalCer/CD1d+ T cells, but considerable numbers of IFN-γ-secreting cells were found among NK1.1−, but not NK1.1+, cells lacking CD4. Thus, NK1.1 surface expression and functional activities of Vα14+ T cells underwent dramatic changes at early stages of listeriosis, and these alterations progressed in a thymus-independent manner. In mutant mice lacking all α-GalCer/CD1d+ T cells listeriosis was ameliorated, suggesting that the subtle contribution of the NK1.1− T-cell subset to antibacterial protection is covered by more profound detrimental effects of the NK1.1+ T-cell subset.

scholarly journals Perforin and Gamma Interferon Are Critical CD8+ T-Cell-Mediated Responses in Vaccine-Induced Immunity against Leishmania amazonensis Infection

2003 ◽  
Vol 71 (6) ◽  
pp. 3172-3182 ◽  
Author(s):  
María Colmenares ◽  
Peter E. Kima ◽  
Erika Samoff ◽  
Lynn Soong ◽  
Diane McMahon-Pratt
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Subset ◽  
Protective Role ◽  
Gamma Interferon ◽  
Leishmania Amazonensis ◽  
Immunological Mechanisms ◽  
Ifn Γ ◽  
Deficient Mice ◽  
Effector Mechanisms

ABSTRACT Previous studies have demonstrated that protection against New World leishmaniasis caused by Leishmania amazonensis can be elicited by immunization with the developmentally regulated Leishmania amastigote antigen, P-8. In this study, several independent experimental approaches were employed to investigate the protective immunological mechanisms involved. T-cell subset depletion experiments clearly indicate that elicitation of CD8+ (as well as CD4+) effector responses is required for protection. Further, mice lacking β2-microglobulin (and hence deficient in major histocompatibility complex class I antigen presentation) were not able to control a challenge infection after vaccination, indicating an essential protective role for CD8+ T effector responses. Analysis of the events ongoing at the cutaneous site of infection indicated a changing cellular dynamic involved in protection. Early postinfection in protectively vaccinated mice, a predominance of CD8+ T cells, secreting gamma interferon (IFN-γ) and expressing perforin, was observed at the site of infection; subsequently, activated CD4+ T cells producing IFN-γ were primarily found. As protection correlated with the ratio of total IFN-γ-producing cells (CD4+ and CD8+ T cells) to macrophages found at the site of infection, a role for IFN-γ was evident; in addition, vaccination of IFN-γ-deficient mice failed to provide protection. To further assess the effector mechanisms that mediate protection, mice deficient in perforin synthesis were examined. Perforin-deficient mice vaccinated with the P-8 antigen were unable to control infection. Thus, the elicitation of CD8+ T cell effector mechanisms (perforin, IFN-γ) are clearly required in the protective immune response against L. amazonensis infection in vaccinated mice.

scholarly journals HLA Class I-T Cell Epitopes from trans-Sialidase Proteins Reveal Functionally Distinct Subsets of CD8+ T Cells in Chronic Chagas Disease

2008 ◽  
Vol 2 (9) ◽  
pp. e288 ◽  
Author(s):  
María G. Alvarez ◽  
Miriam Postan ◽  
D. Brent Weatherly ◽  
María C. Albareda ◽  
John Sidney ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chagas Disease ◽  
Cd8 T Cells ◽  
Hla Class I ◽  
Class I ◽  
T Cell Epitopes ◽  
Chronic Chagas Disease

scholarly journals CD8+ T Cells Participate in the Memory Immune Response to Mycobacterium tuberculosis

2001 ◽  
Vol 69 (7) ◽  
pp. 4320-4328 ◽  
Author(s):  
Natalya V. Serbina ◽  
JoAnne L. Flynn
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Mycobacterium Tuberculosis ◽  
T Cell ◽  
Acute Infection ◽  
Cell Subset ◽  
Ifn Γ ◽  
Memory And Recall ◽  
Memory Immune Response ◽  
Activation Marker Cd69

ABSTRACT The contribution of CD8+ T cells to the control of tuberculosis has been studied primarily during acute infection in mouse models. Memory or recall responses in tuberculosis are less well characterized, particularly with respect to the CD8 T-cell subset. In fact, there are published reports that CD8+ T cells do not participate in the memory immune response to Mycobacterium tuberculosis. We examined the CD8+ T-cell memory and local recall response to M. tuberculosis. To establish a memory immunity model, C57BL/6 mice were infected with M. tuberculosis, followed by treatment with anti-mycobacterial drugs and prolonged rest. The lungs of memory immune mice contained CD4+ and CD8+ T cells with the cell surface phenotype characteristic of memory cells (CD69lowCD25low CD44high). At 1 week postchallenge withM. tuberculosis via aerosol, ≥30% of both CD4+ and CD8+ T cells in the lungs of immune mice expressed the activation marker CD69 and could be restimulated to produce gamma interferon (IFN-γ). In contrast, <6% of T cells in the lungs of naive challenged mice were CD69+ at 1 week postchallenge, and IFN-γ production was not observed at this time point. CD8+ T cells from the lungs of both naive and memory mice after challenge were cytotoxic toward M. tuberculosis-infected macrophages. Our data indicate that memory and recall immunity to M. tuberculosis is comprised of both CD4+ and CD8+ T lymphocytes and that there is a rapid response of both subsets in the lungs following challenge.

scholarly journals Characterization of the Transient Deficiency of PKC Isozyme Levels in Immature Cord Blood T Cells and Its Connection to Anti-Allergic Cytokine Profiles of the Matured Cells

2021 ◽  
Vol 22 (23) ◽  
pp. 12650
Author(s):  
Khalida Perveen ◽  
Alex Quach ◽  
Michael J. Stark ◽  
Susan L. Prescott ◽  
Simon C. Barry ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Interleukin 2 ◽  
Cell Subset ◽  
Necrosis Factor Alpha ◽  
Transient Nature ◽  
Increased Risk ◽  
Pkc Isozymes ◽  
Ifn Γ

Cord blood T cells (CBTC) from a proportion of newborns express low/deficient levels of some protein kinase C (PKC) isozymes, with low levels of PKCζ correlating with increased risk of developing allergy and associated decrease in interferon-gamma (IFN-γ) producing T cells. Interestingly, these lower levels of PKCζ were increased/normalized by supplementing women during pregnancy with n-3 polyunsaturated fatty acids. However, at present, we have little understanding of the transient nature of the deficiency in the neonate and how PKCζ relates to other PKC isozymes and whether their levels influence maturation into IFN-γ producing T cells. There is also no information on PKCζ isozyme levels in the T cell subpopulations, CD4+ and CD8+ cells. These issues were addressed in the present study using a classical culture model of neonatal T cell maturation, initiated with phytohaemagglutinin (PHA) and recombinant human interleukin-2 (rhIL-2). Of the isozymes evaluated, PKCζ, β2, δ, μ, ε, θ and λ/ι were low in CBTCs. The PKC isozyme deficiencies were also found in the CD4+ and CD8+ T cell subset levels of the PKC isozymes correlated between the two subpopulations. Examination of changes in the PKC isozymes in these deficient cells following addition of maturation signals showed a significant increase in expression within the first few hours for PKCζ, β2 and μ, and 1–2 days for PKCδ, ε, θ and λ/ι. Only CBTC PKCζ isozyme levels correlated with cytokine production, with a positive correlation with IFN-γ, interleukin (IL)-2 and tumour necrosis factor-alpha (TNF), and a negative association with IL-9 and IL-10. The findings reinforce the specificity in using CBTC PKCζ levels as a biomarker for risk of allergy development and identify a period in which this can be potentially ‘corrected’ after birth.

scholarly journals Myocardial Gene Expression ofT-bet,GATA-3,Ror-γt,FoxP3, and Hallmark Cytokines in Chronic Chagas Disease Cardiomyopathy: An Essentially Unopposed TH1-Type Response

2014 ◽  
Vol 2014 ◽  
pp. 1-9 ◽  
Author(s):  
Luciana Gabriel Nogueira ◽  
Ronaldo Honorato Barros Santos ◽  
Alfredo Inácio Fiorelli ◽  
Eliane Conti Mairena ◽  
Luiz Alberto Benvenuti ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Chagas Disease ◽  
Cell Subset ◽  
T Cell Subsets ◽  
Relative Contribution ◽  
Heart Donor ◽  
Myocardial Gene Expression ◽  
Type Response ◽  
Chronic Chagas Disease

Background. Chronic Chagas disease cardiomyopathy (CCC), a late consequence ofTrypanosoma cruziinfection, is an inflammatory cardiomyopathy with prognosis worse than those of noninflammatory etiology (NIC). Although the T cell-rich myocarditis is known to play a pathogenetic role, the relative contribution of each of the functional T cell subsets has never been thoroughly investigated. We therefore assessed gene expression of cytokines and transcription factors involved in differentiation and effector function of each functional T cell subset (TH1/TH2/TH17/Treg) in CCC, NIC, and heart donor myocardial samples.Methods and Results. Quantitative PCR showed markedly upregulated expression ofIFN-γand transcription factorT-bet, and minor increases ofGATA-3;FoxP3andCTLA-4;IL-17andIL-18in CCC as compared with NIC samples. Conversely, cytokines expressed byTH2 cells (IL-4,IL-5, andIL-13) or associated with Treg (TGF-βandIL-10) were not upregulated in CCC myocardium. Expression ofTH1-related genes such asT-bet,IFN-γ, andIL-18correlated with ventricular dilation,FoxP3, andCTLA-4.Conclusions. Results are consistent with a strong localTH1-mediated response in most samples, possibly associated with pathological myocardial remodeling, and a proportionally smaller FoxP3+CTLA4+Treg cell population, which is unable to completely curb IFN-γproduction in CCC myocardium, therefore fueling inflammation.

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