Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development

Lee, Seung Joo; McLachlan, James B.; Kurtz, Jonathan R.; Fan, Danhua; Winter, Sebastian; Bäumler, Andreas J.; Jenkins, Marc K.; McSorley, Stephen J.

doi:10.1371/journal.ppat.1002499

Cited by 76 publications

(115 citation statements)

References 60 publications

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“…It is not yet clear why a protein encoded by Salmonella pathogenicity island 2 would be recognized by antibody responses because these proteins would be expected to remain contained within infected cells. However, we have recently identified natural CD4 T-cell epitopes within SPI2 effector proteins (64), and it seems possible that promiscuous secretion of SPI-2 proteins may occur in vivo, as suggested by a recent report (65). Our ability to identify a protective antigen using proteomic screens provides some confidence that other protective antigens are likely to be found among the many target antigens detected in our study.…”

Section: Discussionsupporting

confidence: 63%

Identification of a common immune signature in murine and human systemic Salmonellosis

Lee¹,

Liang

Juárez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Despite the importance of Salmonella infections in human and animal health, the target antigens of Salmonella -specific immunity remain poorly defined. We have previously shown evidence for antibody-mediating protection against invasive Salmonellosis in mice and African children. To generate an overview of antibody targeting in systemic Salmonellosis, a Salmonella proteomic array containing over 2,700 proteins was constructed and probed with immune sera from Salmonella -infected mice and humans. Analysis of multiple inbred mouse strains identified 117 antigens recognized by systemic antibody responses in murine Salmonellosis. Importantly, many of these antigens were independently identified as target antigens using sera from Malawian children with Salmonella bacteremia, validating the study of the murine model. Furthermore, vaccination with SseB, the most prominent antigenic target in Malawian children, provided mice with significant protection against Salmonella infection. Together, these data uncover an overlapping immune signature of disseminated Salmonellosis in mice and humans and provide a foundation for the generation of a protective subunit vaccine.

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Section: Discussionsupporting

confidence: 63%

Identification of a common immune signature in murine and human systemic Salmonellosis

Lee¹,

Liang

Juárez

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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“…Some Th17 effector cells are generated during M. tuberculosis and Salmonella infections (153)(154)(155). Th17 cells might be expected to participate in the control of phagosomal infections by recruiting neutrophils.…”

Section: Srivastava and Ernst Recently Shed Light On How The Interactmentioning

confidence: 99%

CD4⁺T Cells: Guardians of the Phagosome

Tubo

Jenkins

2014

Clin Microbiol Rev

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SUMMARY CD4 + T cells are key cells of the adaptive immune system that use T cell antigen receptors to recognize peptides that are generated in endosomes or phagosomes and displayed on the host cell surface bound to major histocompatibility complex molecules. These T cells participate in immune responses that protect hosts from microbes such as Mycobacterium tuberculosis , Cryptococcus neoformans , Leishmania major , and Salmonella enterica , which have evolved to live in the phagosomes of macrophages and dendritic cells. Here, we review studies indicating that CD4 + T cells control phagosomal infections asymptomatically in most individuals by secreting cytokines that activate the microbicidal activities of infected phagocytes but in a way that inhibits the pathogen but does not eliminate it. Indeed, we make the case that localized, controlled, persistent infection is necessary to maintain large numbers of CD4 + effector T cells in a state of activation needed to eradicate systemic and more pathogenic forms of the infection. Finally, we posit that current vaccines for phagosomal infections fail because they do not produce this “periodic reminder” form of CD4 + T cell-mediated immune control.

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“…Only four I-A b epitopes within Salmonella Typhimurium have been identified to date (25,33,34). While protective responses may be generated against whole protein (33), the protective efficacy of these peptide epitopes has never been demonstrated.…”

Section: Resultsmentioning

confidence: 99%

“…This leads to the potential outcome that peptides from these effector proteins can trigger a memory CD4 T cell response in immunized individuals. Evidence for this comes from our previous work showing a potent CD4 T cell response against peptides derived from Salmonella secreted effector proteins I and J (SseI and SseJ) during active infection (25).…”

mentioning

confidence: 98%

“…We evaluated this hypothesis by comparing the protective capacity of a well-characterized Salmonella CD4 T cell epitope derived from a flagellar protein (FliC) with that of the epitope from the SseI protein, which we have described previously (25). We also investigated the immune responses elicited by this vaccination and the likely contributions of different aspects of the adaptive immune response to protection against infection.…”

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confidence: 99%

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Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection

et al. 2014

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Salmonella infections affect millions worldwide and remain a significant cause of morbidity and mortality. It is known from mouse studies that CD4 T cells are essential mediators of immunity against Salmonella infection, yet it is not clear whether targeting CD4 T cell responses directly with peptide vaccines against Salmonella can be effective in combating infection. Additionally, it is not known whether T cell responses elicited against Salmonella secreted effector proteins can provide protective immunity against infection. In this study, we investigated both of these possibilities using prime-boost immunization of susceptible mice with a single CD4 T cell peptide epitope from Salmonella secreted effector protein I (SseI), a component of the Salmonella type III secretion system. This immunization conferred significant protection against lethal oral infection, equivalent to that conferred by whole heat-killed Salmonella bacteria. Surprisingly, a well-characterized T cell epitope from the flagellar protein FliC afforded no protection compared to immunization with an irrelevant control peptide. The protective response appeared to be most associated with polyfunctional CD4 T cells raised against the SseI peptide, since no antibodies were produced against any of the peptides and very little CD8 T cell response was observed. Overall, this study demonstrates that eliciting CD4 T cell responses against components of the Salmonella type III secretion system can contribute to protection against infection and should be considered in the design of future Salmonella subunit vaccines.

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Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development

Cited by 76 publications

References 60 publications

Identification of a common immune signature in murine and human systemic Salmonellosis

Identification of a common immune signature in murine and human systemic Salmonellosis

CD4⁺T Cells: Guardians of the Phagosome

Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection

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Temporal Expression of Bacterial Proteins Instructs Host CD4 T Cell Expansion and Th17 Development

Cited by 76 publications

References 60 publications

Identification of a common immune signature in murine and human systemic Salmonellosis

Identification of a common immune signature in murine and human systemic Salmonellosis

CD4+T Cells: Guardians of the Phagosome

Vaccination with a Single CD4 T Cell Peptide Epitope from a Salmonella Type III-Secreted Effector Protein Provides Protection against Lethal Infection

Contact Info

Product

Resources

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CD4⁺T Cells: Guardians of the Phagosome