Induction of Protective T Cells againstListeria monocytogenes in Mice by Immunization with a Listeriolysin O-Negative Avirulent Strain of Bacteria and Liposome-Encapsulated Listeriolysin O

ABSTRACT Only listeriolysin O (LLO)-producing strains of Listeria monocytogenes generate protective immunity in mice. Based on the findings that endogenous gamma interferon (IFN-γ) production was induced only by such strains and that purified LLO could induce IFN-γ from NK cells, we have postulated that LLO may play a pivotal role in the induction of Th1-type protective T cells, which are highly dependent on IFN-γ. In this study, mice were immunized with L. monocytogenes ATCC 15313, an LLO-nonproducing avirulent strain, along with LLO encapsulated in liposome (LLO-liposome). LLO-liposome was highly potent in the induction of various cytokines, including IFN-γ. Immunization of mice with either LLO-liposome or the viable strain ATCC 15313 alone did not induce protection against challenge infection. In contrast, the combination of LLO-nonproducing bacteria plus LLO-liposome induced a significant level of protective immunity mediated mainly by Th1-type cells capable of producing a large amount of IFN-γ in an antigen-specific manner. The protection afforded by the combination was not dependent on LLO-specific cytotoxic T cells. These results support the idea that the inability of an LLO-nonproducing avirulent strain or killed bacteria to induce the generation of protective T cells is due not to the lack of a central T-cell epitope(s) but to the lack of ability to induce the production of endogenous cytokine during the early stage of immunization; the results also suggest that an appropriate use of LLO at least in an animal model may be effective in the induction of antigen-specific Th1-dependent protective immunity to various kinds of intracellular parasitic bacteria.

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Insights on the mechanisms of the protective immunity in the brain from the studies on infection with an intracellular microorganism, Toxoplasma gondii

Medical Research Archives ◽

10.18103/mra.v9i11.2597 ◽

2021 ◽

Vol 9 (11) ◽

Author(s):

Yasuhiro Suzuki

Keyword(s):

T Cells ◽

Toxoplasma Gondii ◽

Cd8 T Cells ◽

Protective Immunity ◽

Early Stage ◽

Cytotoxic T Cells ◽

Host Cells ◽

Protective Mechanism ◽

Dependent Manner ◽

The Brain

The immune system operates the protection against infections by selecting efficient pathways depending on the pathogen. Toxoplasma gondii, an obligate intracellular protozoan parasite, has two lifecycle stages, tachyzoite and cyst, in intermediate hosts including humans. Tachyzoite is the acute stage form that quickly proliferates within host cells. Cyst is the chronic stage form that can slowly grow into more than 100 mm in diameter by containing hundreds to thousands of bradyzoites. Our studies on the IFN-g-mediated protective immunity against cerebral tachyzoite growth revealed that IFN-g production by brain-resident cells is not only required for upregulation of the innate protective immunity to limit cerebral tachyzoite proliferation during the early stage of the tachyzoite growth but also crucial for recruiting immune T cells from the periphery and activation of the recruited T cells to ultimately prevent the tachyzoite growth. Since IFN-g is crucial for the protective immunity against various intracellular microorganisms in the brain, it is possible that IFN-gproduced by brain-resident cells plays a key first line defense role by orchestrating both the innate and T cell-mediated protective immunity to control not only T. gondii but also the other intracellular pathogens. Our studies on the protective immunity against T. gondii cysts uncovered the capability of cytotoxic T cells to penetrate into the target in a perforin-dependent manner for its elimination. After penetrating into the target, the cytotoxic T cells secrete granzyme B, which associates with an accumulation of phagocytes to eliminate the parasite. Since the presence of tumor-infiltrating CD8+ T cells in solid cancers is an indicator of positive prognosis of cancer patients, the perforin-mediated penetration of CD8+ T cells and an accumulation of phagocytes could function as a powerful protective mechanism against not only T. gondiicysts but also targets of large mass in general such as solid cancers.

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DNA Sequences Encoding CD4+ and CD8+T-Cell Epitopes Are Important for Efficient Protective Immunity Induced by DNA Vaccination with a Trypanosoma cruziGene

Infection and Immunity ◽

10.1128/iai.69.9.5477-5486.2001 ◽

2001 ◽

Vol 69 (9) ◽

pp. 5477-5486 ◽

Cited By ~ 57

Author(s):

Adriana E. Fujimura ◽

Sheila S. Kinoshita ◽

Vera L. Pereira-Chioccola ◽

Mauricio M. Rodrigues

Keyword(s):

T Cells ◽

T Cell ◽

Dna Sequences ◽

Protective Immunity ◽

Catalytic Domain ◽

Protective Efficacy ◽

Cell Epitope ◽

T Cell Epitopes ◽

Ifn Γ ◽

Domain Iii

ABSTRACT Immunization of BALB/c mice with a plasmid containing the gene forTrypanosoma cruzi trans-sialidase (TS) induced antibodies that inhibited TS enzymatic activity, CD4+ Th1 and CD8+ Tc1 cells, and protective immunity against infection. We used this model to obtain basic information on the requirement of CD4 or CD8 or B-cell epitopes for an effective DNA-induced immunity against T. cruzi infection. For that purpose, mice were immunized with plasmids containing DNA sequences encoding (i) the entire TS protein, (ii) the TS enzymatic domain, (iii) the TS CD4+ T-cell epitopes, (iv) the TS CD8+T-cell epitope, or (v) TS CD4+ and CD8+T-cell epitopes. Plasmids expressing the entire TS or its enzymatic domain elicited similar levels of TS-inhibitory antibodies, γ interferon (IFN-γ)-producing T cells, and protective immunity against infection. Although the plasmid expressing TS CD4 epitopes was immunogenic, its protective efficacy against experimental infection was limited. The plasmid expressing the CD8 epitope was poorly immunogenic and provided little protective immunity. The reason for the limited priming of CD8+ T cells was due to a requirement for CD4+ T cells. To circumvent this problem, a plasmid expressing both CD4+ and CD8+ T-cell epitopes was produced. This plasmid generated levels of IFN-γ-producing T cells and protective immunity comparable to that of the plasmid expressing the entire catalytic domain of TS. Our observations suggest that plasmids expressing epitopes recognized by CD4+ and CD8+ T cells may have a better protective potential against infection with T. cruzi.

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Roles of CD4+ T Cells and Gamma Interferon in Protective Immunity against Babesia microtiInfection in Mice

Infection and Immunity ◽

10.1128/iai.67.8.4143-4148.1999 ◽

1999 ◽

Vol 67 (8) ◽

pp. 4143-4148 ◽

Cited By ~ 55

Author(s):

Ikuo Igarashi ◽

Reiko Suzuki ◽

Seiji Waki ◽

Yoh-Ichi Tagawa ◽

Seyha Seng ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Primary Infection ◽

Protective Immunity ◽

Interleukin 2 ◽

Gamma Interferon ◽

Challenge Infection ◽

Babesia Microti ◽

Spleen Cells ◽

Ifn Γ

ABSTRACT Babesia microti produces a self-limiting infection in mice, and recovered mice are resistant to reinfection. In the present study, the role of T cells in protective immunity against challenge infection was examined. BALB/c mice which recovered from primary infection showed strong protective immunity against challenge infection. In contrast, nude mice which failed to control the primary infection and were cured with an antibabesial drug did not show protection against challenge infection. Treatment of immune mice with anti-CD4 monoclonal antibody (MAb) diminished the protective immunity against challenge infection, but treatment with anti-CD8 MAb had no effect on the protection. Transfer of CD4+ T-cell-depleted spleen cells resulted in higher parasitemia than transfer of CD8+ T-cell-depleted spleen cells. A high level of gamma interferon (IFN-γ), which was produced by CD4+ T cells, was observed for the culture supernatant of spleen cells from immune mice, and treatment of immune mice with anti-IFN-γ MAb partially reduced the protection. Moreover, no protection against challenge infection was found in IFN-γ-deficient mice. On the other hand, treatment of immune mice with MAbs against interleukin-2 (IL-2), IL-4, or tumor necrosis factor alpha did not affect protective immunity. These results suggest essential requirements for CD4+ T cells and IFN-γ in protective immunity against challenge infection with B. microti.

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Circulating CD4 T cells elicited by endemic coronaviruses display vast disparities in abundance and functional potential linked to both antigen specificity and age

The Journal of Infectious Diseases ◽

10.1093/infdis/jiab076 ◽

2021 ◽

Author(s):

Katherine A Richards ◽

Maryah Glover ◽

Jeremy C Crawford ◽

Paul Thomas ◽

Chantelle White ◽

...

Keyword(s):

T Cells ◽

Cd4 T Cells ◽

Protective Immunity ◽

Granzyme B ◽

Antigen Specificity ◽

Functional Potential ◽

Membrane Envelope ◽

Ifn Γ ◽

Human Coronaviruses ◽

Repeated Infections

Abstract Repeated infections with endemic human coronaviruses are thought to reflect lack of long-lasting protective immunity. Here, we evaluate circulating human CD4 T cells collected prior to 2020 for reactivity towards hCoV spike proteins, probing for the ability to produce IFN-γ, IL-2 or granzyme B. We find robust reactivity to spike-derived epitopes, comparable to influenza, but highly variable abundance and functional potential across subjects, depending on age and viral antigen specificity. To explore the potential of these memory cells to be recruited in SARS-CoV-2 infection, we examined the same subjects for cross-reactive recognition of epitopes from SARS-CoV-2 nucleocapsid, membrane/envelope, and spike. The functional potential of these cross-reactive CD4 T cells was highly variable, with nucleocapsid-specific CD4 T cells, but not spike-reactive cells showing exceptionally high levels of granzyme production upon stimulation. These results are considered in light of recruitment of hCoV-reactive cells into responses of humans to SARS-CoV infections or vaccinations.

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Vaccination with DNA Encoding the Immunodominant LACK Parasite Antigen Confers Protective Immunity to Mice Infected with Leishmania major

Journal of Experimental Medicine ◽

10.1084/jem.186.7.1137 ◽

1997 ◽

Vol 186 (7) ◽

pp. 1137-1147 ◽

Cited By ~ 255

Author(s):

Sanjay Gurunathan ◽

David L. Sacks ◽

Daniel R. Brown ◽

Steven L. Reiner ◽

Hughes Charest ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Protective Immunity ◽

Leishmania Major ◽

Protective Efficacy ◽

Dna Vaccination ◽

Attractive Alternative ◽

Dna Immunization ◽

Dna Encoding ◽

Ifn Γ

To determine whether DNA immunization could elicit protective immunity to Leishmania major in susceptible BALB/c mice, cDNA for the cloned Leishmania antigen LACK was inserted into a euykaryotic expression vector downstream to the cytomegalovirus promoter. Susceptible BALB/c mice were then vaccinated subcutaneously with LACK DNA and challenged with L. major promastigotes. We compared the protective efficacy of LACK DNA vaccination with that of recombinant LACK protein in the presence or absence of recombinant interleukin (rIL)-12 protein. Protection induced by LACK DNA was similar to that achieved by LACK protein and rIL-12, but superior to LACK protein without rIL-12. The immunity conferred by LACK DNA was durable insofar as mice challenged 5 wk after vaccination were still protected, and the infection was controlled for at least 20 wk after challenge. In addition, the ability of mice to control infection at sites distant to the site of vaccination suggests that systemic protection was achieved by LACK DNA vaccination. The control of disease progression and parasitic burden in mice vaccinated with LACK DNA was associated with enhancement of antigen-specific interferon-γ (IFN-γ) production. Moreover, both the enhancement of IFN-γ production and the protective immune response induced by LACK DNA vaccination was IL-12 dependent. Unexpectedly, depletion of CD8+ T cells at the time of vaccination or infection also abolished the protective response induced by LACK DNA vaccination, suggesting a role for CD8+ T cells in DNA vaccine induced protection to L. major. Thus, DNA immunization may offer an attractive alternative vaccination strategy against intracellular pathogens, as compared with conventional vaccination with antigens combined with adjuvants.

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Epitope mapping and protective immunity elicited by adenovirus expressing the Leishmania amastigote specific A2 antigen: Correlation with IFN-γ and cytolytic activity by CD8+ T cells

Vaccine ◽

10.1016/j.vaccine.2008.05.091 ◽

2008 ◽

Vol 26 (35) ◽

pp. 4585-4593 ◽

Cited By ~ 44

Author(s):

Daniela M. Resende ◽

Bráulia C. Caetano ◽

Míriam S. Dutra ◽

Marcus L.O. Penido ◽

Christiane F. Abrantes ◽

...

Keyword(s):

T Cells ◽

Cd8 T Cells ◽

Protective Immunity ◽

Epitope Mapping ◽

Cytolytic Activity ◽

Ifn Γ

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Roles of IFN-γ and γδ T Cells in Protective Immunity Against Blood-Stage Malaria

Frontiers in Immunology ◽

10.3389/fimmu.2013.00258 ◽

2013 ◽

Vol 4 ◽

Cited By ~ 39

Author(s):

Shin-Ichi Inoue ◽

Mamoru Niikura ◽

Shoichiro Mineo ◽

Fumie Kobayashi

Keyword(s):

T Cells ◽

Protective Immunity ◽

Γδ T Cells ◽

Blood Stage ◽

Ifn Γ ◽

Blood Stage Malaria

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The shared tumor-associated antigen cytochrome P450 1B1 is recognized by specific cytotoxic T cells

Blood ◽

10.1182/blood-2003-05-1374 ◽

2003 ◽

Vol 102 (9) ◽

pp. 3287-3294 ◽

Cited By ~ 51

Author(s):

Britta Maecker ◽

David H. Sherr ◽

Robert H. Vonderheide ◽

Michael S. von Bergwelt-Baildon ◽

Naoto Hirano ◽

...

Keyword(s):

T Cells ◽

Cytochrome P450 ◽

Cytotoxic T Cells ◽

Phase 1 ◽

Cell Epitope ◽

Target Cells ◽

Cytochrome P450 1B1 ◽

Tumor Associated Antigen ◽

Healthy Donors ◽

Binding Peptides

AbstractCytochrome P450 1B1 (CYP1B1), a drug-metabolizing extrahepatic enzyme, was recently shown to be overexpressed in multiple types of cancer. Such tumor-associated genes may be useful targets for anticancer therapy, particularly cancer immunotherapeutics. We identified HLA-A*0201–binding peptides and a naturally processed and presented T-cell epitope capable of inducing CYP1B1-specific cytotoxic T lymphocytes (CTLs) in HLA-A2 transgenic mice. Furthermore, the induction of CYP1B1-specific T cells was demonstrated in healthy donors and cancer patients. These T cells efficiently lysed target cells pulsed with the cognate peptide. More important, HLA-A2–matched tumor cell lines and primary malignant cells were also recognized by CYP1B1-specific CTLs. These findings form the basis of a phase 1 clinical trial exploring a DNA-based vector encoding CYP1B1 for widely applicable cancer immunotherapy conducted at the Dana-Farber Cancer Institute.

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