scholarly journals Protective Heterologous Immunity against Fatal Ehrlichiosis and Lack of Protection following Homologous Challenge

2008 ◽  
Vol 76 (5) ◽  
pp. 1920-1930 ◽  
Author(s):  
Nagaraja R. Thirumalapura ◽  
Heather L. Stevenson ◽  
David H. Walker ◽  
Nahed Ismail
Keyword(s):  
T Cells ◽  
Persistent Infection ◽  
Secondary Response ◽  
Effector Memory ◽  
Bacterial Clearance ◽  
Igg Antibodies ◽  
Cell Responses ◽  
Ifn Γ ◽  
Memory Type

ABSTRACT The roles of antibodies and memory T cells in protection against virulent Ehrlichia have not been completely investigated. In this study, we addressed these issues by using murine models of mild and fatal ehrlichiosis caused by related monocytotropic Ehrlichia strains. Mice were primed with either Ehrlichia muris or closely related virulent ehrlichiae transmitted by Ixodes ovatus (IOE) ticks given intraperitoneally or intradermally. All groups were reinfected intraperitoneally, 30 days later, with a lethal high dose of IOE. Priming with E. muris, but not IOE, induced strong CD4+ and CD8+ memory type 1 T-cell responses, Ehrlichia-specific immunoglobulin G (IgG) antibodies, and persistent infection. Compared to IOE-primed mice, subsequent lethal IOE challenge of E. muris-primed mice, resulted in (i) 100% protection against lethal infection, (ii) strong Ehrlichia-specific secondary gamma interferon (IFN-γ)-producing effector/effector memory CD4+ and CD8+ T-cell responses, (iii) enhanced secondary anti-ehrlichial antibody response, (iv) accelerated bacterial clearance, and (v) the formation of granulomas in the liver and lung. E. muris-primed mice challenged with IOE had lower levels of serum interleukin-1α (IL-1α), IL-6, and IL-10 compared to unprimed mice challenged with IOE. Interestingly, the fatal secondary response in IOE-primed mice correlated with (i) decline in the Ehrlichia-specific CD4+ and CD8+ type 1 responses, (ii) marked hepatic apoptosis and necrosis, and (iii) substantial bacterial clearance, suggesting that fatal secondary response is due to immune-mediated tissue damage. In conclusion, protection against fatal ehrlichial infection correlates with strong expansion of IFN-γ-producing CD4+ and CD8+ effector memory type 1 T cells, which appear to be maintained in the presence of IgG antibodies and persistent infection.

Effect of a combination therapy between IL-12 and soluble IL-4 receptor (sIL-4R) onCandida albicansand herpes simplex virus type 1 infections in thermally injured mice

2002 ◽  
Vol 48 (10) ◽  
pp. 886-894 ◽  
Author(s):  
Makiko Kobayashi ◽  
Hitoshi Takahashi ◽  
David N Herndon ◽  
Richard B Pollard ◽  
Fujio Suzuki
Keyword(s):  
T Cells ◽  
Candida Albicans ◽  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Herpes Simplex Virus Type ◽  
Cell Responses ◽  
Ifn Γ ◽  
Simplex Virus ◽  
Hsv 1

The effectiveness of a combination using IL-12 and soluble IL-4 receptor (sIL-4R) to treat severe infections of herpes simplex virus type 1 (HSV-1) and Candida albicans in thermally injured mice was investigated. Although sIL-4R decreased burn-associated type 2 T-cell responses, the effect of sIL-4R was minimal on the morbidity and mortality of thermally injured mice exposed to 250 times LD50of HSV-1 or 10 times LD50of C. albicans. Compared with 100% mortality in control mice, mortality for HSV-1 and C. albicans was 40 and 20%, respectively, in thermally injured mice that received IL-12 and sIL-4R in combination. After stimulation with anti-CD3 monoclonal antibody, splenic T cells from thermally injured mice exposed to large amounts of HSV-1 or C. albicans did not produce gamma interferon (IFN-γ) into their culture fluids. However, IFN-γ was produced by splenic T cells from thermally injured and infected mice treated with IL-12 and sIL-4R in combination. These results suggest that therapeutic treatment with a combination of IL-12 and sIL-4R may be effective by inducing type 1 T-cell responses in thermally injured mice exposed to large amounts of HSV-1 or C. albicans.Key words: burn, IL-12, soluble IL-4 receptor, herpesvirus, Candida albicans.

scholarly journals Comparison of Human and Rhesus Macaque T-Cell Responses Elicited by Boosting with NYVAC Encoding Human Immunodeficiency Virus Type 1 Clade C Immunogens

2009 ◽  
Vol 83 (11) ◽  
pp. 5881-5889 ◽  
Author(s):  
Petra Mooij ◽  
Sunita S. Balla-Jhagjhoorsingh ◽  
Niels Beenhakker ◽  
Patricia van Haaften ◽  
Ilona Baak ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
T Cell ◽  
Interleukin 2 ◽  
T Cell Responses ◽  
Effector Memory ◽  
Data Set ◽  
Cell Responses ◽  
Immunodeficiency Virus ◽  
Ifn Γ

ABSTRACT Rhesus macaques (Macaca mulatta) have played a valuable role in the development of human immunodeficiency virus (HIV) vaccine candidates prior to human clinical trials. However, changes and/or improvements in immunogen quality in the good manufacturing practice (GMP) process or changes in adjuvants, schedule, route, dose, or readouts have compromised the direct comparison of T-cell responses between species. Here we report a comparative study in which T-cell responses from humans and macaques to HIV type 1 antigens (Gag, Pol, Nef, and Env) were induced by the same vaccine batches prepared under GMP and administered according to the same schedules in the absence and presence of priming. Priming with DNA (humans and macaques) or alphavirus (macaques) and boosting with NYVAC induced robust and broad antigen-specific responses, with highly similar Env-specific gamma interferon (IFN-γ) enzyme-linked immunospot assay responses in rhesus monkeys and human volunteers. Persistent cytokine responses of antigen-specific CD4+ and CD8+ T cells of the central memory as well as the effector memory phenotype, capable of simultaneously eliciting multiple cytokines (IFN-γ, interleukin 2, and tumor necrosis factor alpha), were induced. Responses were highly similar in humans and primates, confirming earlier data indicating that priming is essential for inducing robust NYVAC-boosted IFN-γ T-cell responses. While significant similarities were observed in Env-specific responses in both species, differences were also observed with respect to responses to other HIV antigens. Future studies with other vaccines using identical lots, immunization schedules, and readouts will establish a broader data set of species similarities and differences with which increased confidence in predicting human responses may be achieved.

scholarly journals Peptides Derived From S and N Proteins of Severe Acute Respiratory Syndrome Coronavirus 2 Induce T Cell Responses: A Proof of Concept for T Cell Vaccines

2021 ◽  
Vol 12 ◽  
Author(s):  
Yu-Sun Lee ◽  
So-Hee Hong ◽  
Hyo-Jung Park ◽  
Ho-Young Lee ◽  
Ji-Yeon Hwang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Severe Acute Respiratory Syndrome ◽  
T Cell Responses ◽  
Effector Memory ◽  
Target Cells ◽  
Dependent Manner ◽  
Peptide Vaccines ◽  
Cell Responses ◽  
Ifn Γ

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that escape vaccine-induced neutralizing antibodies has indicated the importance of T cell responses against this virus. In this study, we highlight the SARS-CoV-2 epitopes that induce potent T cell responses and discuss whether T cell responses alone are adequate to confer protection against SARS-CoV-2 and describe the administration of 20 peptides with an RNA adjuvant in mice. The peptides have been synthesized based on SARS-CoV-2 spike and nucleocapsid protein sequences. Our study demonstrates that immunization with these peptides significantly increases the proportion of effector memory T cell population and interferon-γ (IFN-γ)-, interleukin-4 (IL-4)-, tumor necrosis factor-α (TNF-α)-, and granzyme B-producing T cells. Of these 20 peptides, four induce the generation of IFN-γ-producing T cells, elicit CD8+ T cell (CTL) responses in a dose-dependent manner, and induce cytotoxic T lymphocytes that eliminate peptide-pulsed target cells in vivo. Although it is not statistically significant, these peptide vaccines reduce viral titers in infected hamsters and alleviate pulmonary pathology in SARS-CoV-2-infected human ACE2 transgenic mice. These findings may aid the design of effective SARS-CoV-2 peptide vaccines, while providing insights into the role of T cells in SARS-CoV-2 infection.

scholarly journals LACK-Specific CD4+ T Cells That Induce Gamma Interferon Production in Patients with Localized Cutaneous Leishmaniasis during an Early Stage of Infection

2002 ◽  
Vol 70 (6) ◽  
pp. 3122-3129 ◽  
Author(s):  
Eliane Bourreau ◽  
Ghislaine Prévot ◽  
Jacques Gardon ◽  
Roger Pradinaud ◽  
Hitoshi Hasagewa ◽  
...  
Keyword(s):  
T Cells ◽  
Early Stage ◽  
Interleukin 10 ◽  
Gamma Interferon ◽  
Effector Memory ◽  
Cellular Source ◽  
Effector Memory Cells ◽  
Ifn Γ

ABSTRACT The profile of cytokines induced by soluble leishmania antigen (SLA) and the Leishmania homologue of the mammalian receptor for activated C kinase (LACK), a candidate vaccine against leishmaniasis, and the cellular source of the cytokines produced in response to these antigens were analyzed in patients infected with Leishmania guyanensis. Gamma interferon (IFN-γ) and interleukin-10 (IL-10) were produced in response to LACK. Although LACK-specific CD4+ cells producing IFN-γ were isolated only during the early phase of infection (less than 30 days following the onset of infection), cells producing IL-10 in response to LACK were detected in all patients. CD4+ T cells producing IFN-γ and IL-13 were produced in response to SLA in all patients. SLA- and LACK-specific T cells are effector memory cells, as they are CD45RA− CCR7− CD4+ T cells. CD4+ T cells producing IFN-γ are CD62L−, and CD4+ T cells producing IL-10 are CD62L+, indicating that these cells have different tissue-homing capacities. These findings show that SLA and LACK induce both type 1 (IFN-γ) and type 2 (IL-10 or IL-13) cell responses.

scholarly journals Peripheral CD8 effector-memory type 1 T-cells correlate with outcome in ipilimumab-treated stage IV melanoma patients

2017 ◽  
Vol 73 ◽  
pp. 61-70 ◽  
Author(s):  
Kilian Wistuba-Hamprecht ◽  
Alexander Martens ◽  
Florian Heubach ◽  
Emanuela Romano ◽  
Marnix Geukes Foppen ◽  
...  
Keyword(s):  
T Cells ◽  
Stage Iv ◽  
Effector Memory ◽  
Melanoma Patients ◽  
Memory Type ◽  
Stage Iv Melanoma

scholarly journals Adaptive immune responses to SARS-CoV-2 in recovered severe COVID-19 patients

2021 ◽  
Author(s):  
Beatriz Olea ◽  
Eliseo Albert ◽  
Ignacio Torres ◽  
Paula Amat ◽  
María José Remigia ◽  
...  
Keyword(s):  
T Cells ◽  
Serum Levels ◽  
Igg Antibodies ◽  
Cell Responses ◽  
Adaptive Immune ◽  
Specific Serum ◽  
M Proteins ◽  
Specific Igg ◽  
Ifn Γ ◽  
Over Time

ABSTRACTObjectivesThere is an imperative need to determine the durability of adaptive immunity to SARS-CoV-2. We enumerated SARS-CoV-2-reactive CD4+ and CD8+ T cells targeting S1 and M proteins and measured RBD-specific serum IgG over a period of 2-6 months after symptoms onset in a cohort of subjects who had recovered from severe clinical forms of COVID-19.MethodsWe recruited 58 patients (38 males and 20 females; median age, 62.5 years), who had been hospitalized with bilateral pneumonia, 60% with one or more comorbidities. IgG antibodies binding to SARS-CoV-2 RBD were measured by ELISA. SARS-CoV-2-reactive CD69+-expressing-IFNγ-producing-CD4+ and CD8+ T cells were enumerated in heparinized whole blood by flow cytometry for ICS.ResultsDetectable SARS-CoV-2-S1/M-reactive CD69+-IFN-γ CD4+ and CD8+ T cells were displayed in 17 (29.3%) and 6 (10.3%) subjects respectively, at a median of 84 days after onset of symptoms (range, 58-191 days). Concurrent comorbidities increased the risk (OR, 3.15; 95% CI, 1.03-9.61; P=0.04) of undetectable T-cell responses in models adjusted for age, sex and hospitalization ward. Twenty-one out of the 35 patients (60%) had detectable RBD-specific serum IgGs at a median of 118 days (range, 60 to 145 days) after symptoms onset. SARS-CoV-2 RBD-specific IgG serum levels were found to drop significantly over time.ConclusionA relatively limited number of subjects who developed severe forms of COVID-19 had detectable SARS-CoV-2-S1/M IFNγ CD4+ and CD8+ T cells at midterm after clinical diagnosis. Our data also indicated that serum levels of RBD-specific IgGs decline over time, becoming undetectable in some patients.

scholarly journals Interferon-Inducible Protein 10, but Not Monokine Induced by Gamma Interferon, Promotes Protective Type 1 Immunity in Murine Klebsiella pneumoniae Pneumonia

2005 ◽  
Vol 73 (12) ◽  
pp. 8226-8236 ◽  
Author(s):  
Xianying Zeng ◽  
Thomas A. Moore ◽  
Michael W. Newstead ◽  
Jane C. Deng ◽  
Steven L. Kunkel ◽  
...  
Keyword(s):  
T Cells ◽  
Klebsiella Pneumoniae ◽  
Γδ T Cells ◽  
Gamma Interferon ◽  
Bacterial Clearance ◽  
Transgenic Expression ◽  
Ifn Γ ◽  
Inducible Protein ◽  
Interferon Inducible Protein

ABSTRACT CXC chemokines that lack the ELR motif, including interferon-inducible protein 10 [IP-10 (CXCL10)] and monokine induced by gamma interferon (IFN-γ) [MIG (CXCL9)], have been shown to mediate the generation of type 1 immune responses. In this study, we found that intrapulmonary administration of the gram-negative bacterium Klebsiella pneumoniae resulted in the local and systemic expression of IP-10, followed sequentially by MIG expression. MIG mRNA expression in the lungs of Klebsiella-infected mice required the endogenous production of IFN-γ, whereas IP-10 was expressed in both an IFN-γ-dependent and an IFN-γ-independent fashion. Antibody-mediated neutralization of IP-10 resulted in reduced bacterial clearance and decreased survival, whereas bacterial clearance was unaltered in mice treated with anti-MIG antibody. Impaired bacterial clearance in anti-IP-10 antibody-treated mice was associated with significant reductions in the number and/or activational status of NK and NK-T cells, CD4+ T cells, and γδ T cells, as well as a reduction in the expression of IFN-γ. Conversely, the transient transgenic expression of murine IP-10 using adenovirus-mediated gene transfer resulted in improved bacterial clearance when IP-10 adenovirus was given concomitant with intrapulmonary bacterial challenge. These results indicate that IP-10 is an important component of innate immunity against extracellular bacterial pathogens of the lung and may represent a candidate molecule for immunotherapy in the setting of severe respiratory tract infection.

Safety and immunogenicity of tyrosinase DNA vaccines in patients with melanoma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3005-3005 ◽  
Author(s):  
J. D. Wolchok ◽  
H. Gallardo ◽  
M. Perales ◽  
T. Rasalan ◽  
J. Wang ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Dna Vaccines ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Antibody Responses ◽  
Effector Memory ◽  
Cell Responses ◽  
Ifn Γ

3005 Background: T-cell and antibody responses to self antigens on cancer are usually constrained by immunologic tolerance and ignorance. We found that DNA vaccines encoding xenogeneic differentiation antigens, such as tyrosinase (TYR), can mediate tumor protection and regression in implantable mouse models and dogs with spontaneously arising melanoma. Based on this, we conducted a trial of DNA vaccines encoding mouse and human TYR in patients with AJCC stage III/IV melanoma. Methods: HLA-A*0201+ melanoma patients were randomized to 2 different schedules: one group received 3 injections of mouse TYR DNA followed by 3 injections of human TYR DNA while the other group received 3 injections of human TYR DNA followed by 3 injections with the mouse gene. The study was conducted a three different dose levels: 100, 500 and 1,500 mcg DNA/injection, administered IM every 3 weeks. A total of 18 patients were treated, 6 at each dose level being randomized to one of the two schedules. Anti-TYR antibodies and CD8+ T cells recognizing the native human tyrosinase369-377 (YMDGTMSQV) peptide were measured at fixed time points. T-cell responses were monitored with MHC tetramer and intracytoplasmic IFN-γ staining assays using 10-day in vitro stimulation. Multiparametric flow cytometry was performed to further define the phenotype of responding cells. Results: Most toxicities were transient grade I injection site reactions. Seven patients had CD8+ T cell responses, defined as a >3 standard deviation increase in baseline reactivity to the TYR peptide in either the tetramer or intracellular IFN-γ assay. There was no relationship between dose level or assigned schedule and occurrence of T-cell response. Phenotypic characterization of responding T cells showed that most were consistent with an effector memory phenotype including the expression of granzyme B and surface expression of CD107a. No antibody responses were observed. At a median of 42 months of follow-up, median survival has not been reached and 6/18 patients have died from melanoma (1 in the group of patients who had a T cell response and 5 in the non-responders). Conclusions: Mouse and human TYR DNA vaccines were safe and induced CD8+ T cell responses in 7/18 patients. T cells recognizing a native TYR peptide had a phenotype consistent with that of effector memory cells. No significant financial relationships to disclose.

scholarly journals α-NAC–Specific Autoreactive CD8+ T Cells in Atopic Dermatitis Are of an Effector Memory Type and Secrete IL-4 and IFN-γ

2016 ◽  
Vol 196 (8) ◽  
pp. 3245-3252 ◽  
Author(s):  
Lennart M. Roesner ◽  
Annice Heratizadeh ◽  
Susanne Wieschowski ◽  
Irene Mittermann ◽  
Rudolf Valenta ◽  
...  
Keyword(s):  
T Cells ◽  
Atopic Dermatitis ◽  
Cd8 T Cells ◽  
Effector Memory ◽  
Ifn Γ ◽  
Memory Type

scholarly journals Augmentation of HIV-specific T cell function by immediate treatment of hyperacute HIV-1 infection

2019 ◽  
Vol 11 (493) ◽  
pp. eaau0528 ◽  
Author(s):  
Zaza M. Ndhlovu ◽  
Samuel W. Kazer ◽  
Thandeka Nkosi ◽  
Funsho Ogunshola ◽  
Daniel M. Muema ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
T Cell Responses ◽  
Transcriptional Analysis ◽  
Effector Memory ◽  
Strong Positive Correlation ◽  
Cell Responses ◽  
Ifn Γ ◽  
The Impact

Sustained viremia after acute HIV infection is associated with profound CD4+T cell loss and exhaustion of HIV-specific CD8+T cell responses. To determine the impact of combination antiretroviral therapy (cART) on these processes, we examined the evolution of immune responses in acutely infected individuals initiating treatment before peak viremia. Immediate treatment of Fiebig stages I and II infection led to a rapid decline in viral load and diminished magnitude of HIV-specific (tetramer+) CD8+T cell responses compared to untreated donors. There was a strong positive correlation between cumulative viral antigen exposure before full cART-induced suppression and immune responses measured by MHC class I tetramers, IFN-γ ELISPOT, and CD8+T cell activation. HIV-specific CD8+T responses of early treated individuals were characterized by increased CD127 and BCL-2 expression, greater in vitro IFN-γ secretion, and enhanced differentiation into effector memory (Tem) cells. Transcriptional analysis of tetramer+CD8+T cells from treated persons revealed reduced expression of genes associated with activation and apoptosis, with concurrent up-regulation of prosurvival genes includingBCL-2,AXL, andSRC. Early treatment also resulted in robust HIV-specific CD4+T cell responses compared to untreated HIV-infected individuals. Our data show that limiting acute viremia results in enhanced functionality of HIV-specific CD4+and CD8+T cells, preserving key antiviral properties of these cells.

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