Listeriolysin O, a cytolysin derived from Listeria monocytogenes, inhibits generation of ovalbumin-specific Th2 immune response by skewing maturation of antigen-specific T cells into Th1 cells

The immunologic mechanism of protective immunity to the intracellular parasite Listeria monocytogenes (Lm) is not well understood, however, antilisterial immunity can be adoptively transferred with T lymphocytes from Lm-immune donors. The Lm-immune cells are believed to produce macrophage-activating lymphokines, which leads to the eventual macrophage-dependent eradication of the bacterium. Increasing evidence suggests that immunity to Lm resides exclusively within the CD8+ T cell subset. It is possible that the Lm-immune CD8+ T cells function to release sequestered Lm from nonprofessional phagocytes to awaiting activated macrophage populations. This study was conducted to determine if listeriolysin O (LLO), which is an essential determinant of Lm pathogenicity, is also a target of the antilisterial immune response. We have found that target cells infected with a LLO+ Lm strain are lysed by Lm-immune cytotoxic cells, whereas target cells infected with a LLO- Lm mutant, or pulsed with a heat-killed Lm preparation, are not lysed by the Lm-immune effector cells. We have used a Bacillus subtilis (Bs) construct that expresses the LLO gene product and found that target cells infected with the LLO+ Bs construct are lysed by antilisterial cytotoxic cells. The antilisterial cytotoxic response is targeted against LLO, in that we have also used a Bs construct that expresses the perfringolysin (PLO) gene product and found that target cells infected with the PLO+ Bs are not lysed by antilisterial cytotoxic effector cells. These data strongly suggest that LLO is a target antigen of antilisterial immunity and may represent the dominant target during the expression of the immune response to Lm.

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The depletion of Foxp3+/CD25+ regulatory T cells drives a Th2 immune response and reduces severity in a mouse model of acute pancreatitis.

Pancreatology ◽

10.1016/j.pan.2019.05.060 ◽

2019 ◽

Vol 19 ◽

pp. S26

Author(s):

Juliane Glaubitz ◽

Anika Wilden ◽

Cindy van den Brandt ◽

Frank Ulrich Weiss ◽

Julia Mayerle ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Acute Pancreatitis ◽

Regulatory T Cells ◽

Mouse Model ◽

Th2 Immune Response

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Listeria monocytogenes as a Short-Lived Delivery System for the Induction of Type 1 Cell-Mediated Immunity against the p36/LACK Antigen of Leishmania major

Infection and Immunity ◽

10.1128/iai.68.3.1498-1506.2000 ◽

2000 ◽

Vol 68 (3) ◽

pp. 1498-1506 ◽

Cited By ~ 35

Author(s):

Neirouz Soussi ◽

Geneviève Milon ◽

Jean-Hervé Colle ◽

Evelyne Mougneau ◽

Nicolas Glaichenhaus ◽

...

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Cd4 T Cells ◽

Leishmania Major ◽

Ex Vivo ◽

Experimental Models ◽

Interleukin 4 ◽

Cell Mediated Immunity ◽

Th1 Cells ◽

Ifn Γ

ABSTRACT Listeria monocytogenes has been used as an experimental live vector for the induction of CD8-mediated immune responses in various viral and tumoral experimental models. Susceptibility of BALB/c mice to Leishmania major infection has been correlated to the preferential development of Th2 CD4 T cells through an early production of interleukin 4 (IL-4) by a restricted population of CD4 T cells which react to a single parasite antigen, LACK (stands forLeishmania homologue of receptors for activated C kinase). Experimental vaccination with LACK can redirect the differentiation of CD4+ T cells towards the Th1 pathway if LACK is coadministrated with IL-12. As IL-12 is known to be induced by L. monocytogenes, we have tested the ability of a recombinant attenuated actA mutant L. monocytogenes strain expressing LACK to induce the development of LACK-specific Th1 cells in both B10.D2 and BALB/c mice, which are resistant and susceptible toL. major, respectively. After a single injection of LACK-expressing L. monocytogenes, IL-12/p40 transcripts showed a rapid burst, and peaks of gamma interferon (IFN-γ)-secreting LACK-specific Th1 cells were detected around day 5 in the spleens and livers of mice of both strains. These primed IFN-γ-secreting LACK-reactive T cells were not detected ex vivo after day 7 of immunization but could be recruited and detected 15 days later in the draining lymph node after an L. major footpad challenge. Although immunization of BALB/c mice with LACK-expressing L. monocytogenes did not change the course of the infection withL. major, immunized B10.D2 mice exhibited significantly smaller lesions than nonimmunized controls. Thus, our results demonstrate that, in addition of its recognized use for the induction of effector CD8 T cells, L. monocytogenes can also be used as a live recombinant vector to favor the development of potentially protective IFN-γ-secreting Th1 CD4 T lymphocytes.

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Expression of two Listeria monocytogenes antigens (P60 and LLO) in Lactococcus lactis and examination for use as live vaccine vectors

Journal of Medical Microbiology ◽

10.1099/jmm.0.018770-0 ◽

2010 ◽

Vol 59 (8) ◽

pp. 904-912 ◽

Cited By ~ 20

Author(s):

Mohammed Bahey-El-Din ◽

Pat G. Casey ◽

Brendan T. Griffin ◽

Cormac G. M. Gahan

Keyword(s):

Immune Response ◽

Listeria Monocytogenes ◽

Lactococcus Lactis ◽

Protective Efficacy ◽

Oral Immunization ◽

Listeriolysin O ◽

Oral Vaccination ◽

Vaccine Vectors ◽

Food Borne ◽

Presentation Pathway

Listeria monocytogenes is a food-borne intracellular pathogen that mainly infects pregnant and immunocompromised individuals. The pore-forming haemolysin listeriolysin O (LLO), the main virulence factor of Listeria monocytogenes, allows bacteria to escape from the harsh environment of the phagosome to the cytoplasm of the infected cell. This leads to processing of bacterial antigens predominantly through the cytosolic MHC class I presentation pathway. We previously engineered the food-grade bacterium Lactococcus lactis to express LLO and demonstrated an LLO-specific CD8+ response upon immunization of mice with the engineered L. lactis vaccine strains. In the present work, we examined the immune response and protective efficacy of an L. lactis strain co-expressing LLO and a truncated form of the listerial P60 antigen (tP60). Oral immunization revealed no significant protection against listeriosis with L. lactis expressing LLO, tP60 or the combined LLO/tP60. In contrast, intraperitoneal vaccination induced an LLO-specific CD8+ immune response with LLO-expressing L. lactis but no significant improvement in protection was observed following vaccination with the combined LLO/tP60 expressing L. lactis strain. This may be due to the low level of tP60 expression in the LLO/tP60 strain. These results demonstrate the necessity for improved oral vaccination strategies using LLO-expressing L. lactis vaccine vectors.

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CD39 is upregulated during activation of mouse and human T cells and attenuates the immune response to Listeria monocytogenes

PLoS ONE ◽

10.1371/journal.pone.0197151 ◽

2018 ◽

Vol 13 (5) ◽

pp. e0197151 ◽

Cited By ~ 17

Author(s):

Friederike Raczkowski ◽

Anne Rissiek ◽

Isabell Ricklefs ◽

Kirsten Heiss ◽

Valéa Schumacher ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Listeria Monocytogenes ◽

Human T Cells

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Cytolysin-Dependent Escape of the Bacterium from the Phagosome Is Required but Not Sufficient for Induction of the Th1 Immune Response against Listeria monocytogenes Infection: Distinct Role of Listeriolysin O Determined by Cytolysin Gene Replacement

Infection and Immunity ◽

10.1128/iai.01779-06 ◽

2007 ◽

Vol 75 (8) ◽

pp. 3791-3801 ◽

Cited By ~ 26

Author(s):

Hideki Hara ◽

Ikuo Kawamura ◽

Takamasa Nomura ◽

Takanari Tominaga ◽

Kohsuke Tsuchiya ◽

...

Keyword(s):

Immune Response ◽

Listeria Monocytogenes ◽

Virulence Factor ◽

Protective Immunity ◽

Gene Replacement ◽

Listeriolysin O ◽

Listeria Ivanovii ◽

Ifn Γ

ABSTRACT Listeria monocytogenes evades the antimicrobial mechanisms of macrophages by escaping from the phagosome into the cytosolic space via a unique cytolysin that targets the phagosomal membrane, listeriolysin O (LLO), encoded by hly. Gamma interferon (IFN-γ), which is known to play a pivotal role in the induction of Th1-dependent protective immunity in mice, appears to be produced, depending on the bacterial virulence factor. To determine whether the LLO molecule (the major virulence factor of L. monocytogenes) is indispensable or the escape of bacteria from the phagosome is sufficient to induce IFN-γ production, we first constructed an hly-deleted mutant of L. monocytogenes and then established isogenic L. monocytogenes mutants expressing LLO or ivanolysin O (ILO), encoded by ilo from Listeria ivanovii. LLO-expressing L. monocytogenes was highly capable of inducing IFN-γ production and Listeria-specific protective immunity, while the hly-deleted mutant was not. In contrast, the level of IFN-γ induced by ILO-expressing L. monocytogenes was significantly lower both in vitro and in vivo, despite the ability of this strain to escape the phagosome and the intracellular multiplication at a level equivalent to that of LLO-expressing L. monocytogenes. Only a negligible level of protective immunity was induced in mice against challenge with LLO- and ILO-expressing L. monocytogenes. These results clearly show that escape of the bacterium from the phagosome is a prerequisite but is not sufficient for the IFN-γ-dependent Th1 response against L. monocytogenes, and some distinct molecular nature of LLO is indispensable for the final induction of IFN-γ that is essentially required to generate a Th1-dependent immune response.

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FOXP3+ T-CELLS AND TH2 IMMUNE RESPONSE SHIFT ARE INDUCED BY LOCAL EXPRESSION OF INDOLEAMINE 2,3 DIOXYGENASE IN A COMPOSITE ISLET GRAFT

Transplantation Journal ◽

10.1097/00007890-201007272-00593 ◽

2010 ◽

Vol 90 ◽

pp. 314

Author(s):

R. B. jalili ◽

A. Moeen ◽

R. Hartwell ◽

G. Warnock ◽

B. Larijani ◽

...

Keyword(s):

Immune Response ◽

T Cells ◽

Response Shift ◽

Islet Graft ◽

Indoleamine 2,3 Dioxygenase ◽

Th2 Immune Response ◽

Local Expression

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Multiple Mechanisms Contribute to the Robust Rapid Gamma Interferon Response by CD8+ T Cells during Listeria monocytogenes Infection

Infection and Immunity ◽

10.1128/iai.01207-08 ◽

2009 ◽

Vol 77 (4) ◽

pp. 1492-1501 ◽

Cited By ~ 10

Author(s):

Elsa N. Bou Ghanem ◽

Denise S. McElroy ◽

Sarah E. F. D'Orazio

Keyword(s):

T Cells ◽

Listeria Monocytogenes ◽

Gamma Interferon ◽

Interferon Response ◽

In Vitro Assays ◽

Interleukin 12 ◽

Dependent Manner ◽

Listeriolysin O ◽

Ifn Γ ◽

Bacterial Products

ABSTRACT A subset of CD8+ T cells can rapidly secrete gamma interferon (IFN-γ) in an antigen-independent and interleukin-12 (IL-12)- and IL-18-dependent manner within 16 h of infection with the intracellular bacterial pathogen Listeria monocytogenes. This rapid IFN-γ response is robust enough to be detected directly ex vivo and is not observed following infection with intracellular bacterial pathogens that remain sequestered within host cell vacuoles. We demonstrate here that three distinct pathways can lead to rapid secretion of IFN-γ by CD8+ T cells during L. monocytogenes infection: (i) a direct cytokine-inducing activity encoded by the cholesterol-dependent cytolysin (CDC) listeriolysin O (LLO) acts within the infected cell, (ii) the pore-forming activity of LLO promotes cytosolic localization of bacterial products that trigger cytosol-specific signaling pathways, and (iii) the sustained presence of high concentrations of bacterial products can exogenously trigger cytokine production. Although it has been suggested that CDC protein toxins may act as Toll-like receptor 4 (TLR4) agonists to trigger proinflammatory cytokine secretion, we show in this report that TLR4 signaling is not required to induce a maximal rapid IFN-γ response by CD8+ T cells. The results presented here indicate that multiple mechanisms contribute to the induction of rapid IFN-γ secretion by CD8+ T cells during Listeria infection and that care must be taken when interpreting the results of in vitro assays, since the contribution of each pathway can vary depending on how the assay is performed.

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Memory CD8+ T Cells Provide Innate Immune Protection against Listeria monocytogenes in the Absence of Cognate Antigen

Journal of Experimental Medicine ◽

10.1084/jem.20031051 ◽

2003 ◽

Vol 198 (10) ◽

pp. 1583-1593 ◽

Cited By ~ 230

Author(s):

Rance E. Berg ◽

Emily Crossley ◽

Sean Murray ◽

James Forman

Keyword(s):

Immune Response ◽

T Cells ◽

Listeria Monocytogenes ◽

Innate Immune Response ◽

Cd8 T Cells ◽

Primary Source ◽

Innate Immune ◽

Memory Cd8 T Cells ◽

Cognate Antigen ◽

Ifn Γ

Interferon (IFN)-γ plays an important role in the innate immune response against intracellular bacterial pathogens. It is commonly thought that natural killer cells are the primary source of this cytokine that is involved in activating antibacterial effects in infected cells and polarizing CD4+ T cells toward the Th1 subset. However, here we show that both effector and memory CD8+ T cells have the potential to secrete IFN-γ in response to interleukin (IL)-12 and IL-18 in the absence of cognate antigen. We demonstrate that memory CD8+ T cells specific for the ovalbumin protein secrete IFN-γ rapidly after infection with wild-type Listeria monocytogenes (LM). Furthermore, small numbers of ovalbumin-specific, memory CD8+ T cells can reduce spleen and liver bacterial counts in IFN-γ–deficient mice 3 d after LM infection. Up-regulation of the receptors for IL-12 and IL-18 provides a mechanism for the ability of memory CD8+ T cells to respond in this antigen nonspecific manner. Thus, CD8+ T cells play an important role in the innate immune response against intracellular pathogens by rapidly secreting IFN-γ in response to IL-12 and IL-18.

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