Processing of viable Salmonella typhimurium for presentation of a CD4 T cell epitope from the Salmonella invasion protein C (SipC)

ABSTRACTThe apicomplexan parasiteToxoplasma gondiican cause severe disease in immunocompromised individuals. Previous studies in mice have focused largely on CD8+T cells, and the role of CD4 T cells is relatively unexplored. Here, we show that immunization of the C57BL/6 strain of mice, in which the immunodominant CD8 T cell response to the parasite dense-granule protein GRA6 cannot be generated, leads to a prominent CD4 T cell response. To identify the CD4 T cell-stimulating antigens, we generated aT. gondii-specific,lacZ-inducible, CD4 T cell hybridoma and used it as a probe to screen aT. gondiicDNA library. We isolated a cDNA encoding a protein of unknown function that we call CD4Ag28m and identified the minimal peptide, AS15, which was presented by major histocompatibility complex (MHC) class II molecules to the CD4 T cells. Immunization of mice with the AS15 peptide provided significant protection against subsequent parasite challenge, resulting in a lower parasite burden in the brain. Our findings identify the first CD4 T cell-stimulating peptide that can confer protection against toxoplasmosis and provide an important tool for the study of CD4 T cell responses and the design of effective vaccines against the parasite.

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“…Currently, CD4 epitopes for pathogens such as Salmonella spp. (12,42), Mycobacterium spp. (1,20,63), Trypanosoma cruzi (26), Leishmania spp.…”

Section: Discussionmentioning

confidence: 99%

The Toxoplasma gondii Peptide AS15 Elicits CD4 T Cells That Can Control Parasite Burden

et al. 2012

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“…Very few Ags have been defined as targets of Salmonella-specific CD4 T cells, and even fewer MHC class II epitopes have been mapped (12,13,22). Therefore, it is not yet clear whether SM1 T cells represent an unusual CD4 T cell population, or whether they are representative of the endogenous Salmonella-specific CD4 T cell response.…”

Section: Discussionmentioning

confidence: 99%

Low-DoseSalmonellaInfection Evades Activation of Flagellin-Specific CD4 T Cells

Srinivasan

Foley

Ravindran

et al. 2004

The Journal of Immunology

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Many pathogens can establish a lethal infection from relatively small inocula, yet the effect of infectious dose upon CD4 T cell activation is not clearly understood. This issue was examined by tracking Salmonella flagellin-specific SM1 T cells in vivo, after i.v. and oral challenge of mice with virulent Salmonella typhimurium. SM1 T cells rapidly expressed activation markers and expanded in response to high-dose infection but remained completely unresponsive in mice challenged with low doses of Salmonella. SM1 T cells, in these mice, remained unresponsive, despite massive bacterial replication in vivo. Naive SM1 T cells in low-dose Salmonella-infected mice were activated rapidly after the injection of flagellin peptide, demonstrating that these T cells were fully capable of responding, ruling out the possibility of a bacterial-induced suppressive environment. The inability of flagellin-specific SM1 T cells to respond to low-dose infection was not due to Ag down-regulation, because flagellin expression was detected using a functional assay. Together, these data suggest that low-dose Salmonella infection can evade flagellin-specific CD4 T cell activation in vivo.

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“…Few tools are currently available to follow the CD4 ϩ T cell-specific immunity induced by live bacteria during Salmonella infection. For example, T cell clones specific for FliC or SipC are known (27,28), but analyses of responses to these Ags did not appear useful, because expression is down-regulated after host invasion (29,30). We also excluded the use of OVA-expressing Salmonella as a reporter system, because expression of a foreign Ag can affect the virulence of the bacteria (31).…”

Section: Adaptive Immune Response To Salmonella Is Affected By Spi2 Fmentioning

confidence: 99%

Intracellular Salmonella Inhibit Antigen Presentation by Dendritic Cells

Cheminay

Möhlenbrink

Hensel

2005

The Journal of Immunology

154

162

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Dendritic cells (DC) are important APCs linking innate and adaptive immunity. During analysis of the intracellular activities of Salmonella enterica in DC, we observed that viable bacteria suppress Ag-dependent T cell proliferation. This effect was dependent on the induction of inducible NO synthase by DC and on the function of virulence genes in Salmonella pathogenicity island 2 (SPI2). Intracellular activities of Salmonella did not affect the viability, Ag uptake, or maturation of DC, but resulted in reduced presentation of antigenic peptides by MHC class II molecules. Increased resistance to reinfection was observed after vaccination of mice with SPI2-deficient Salmonella compared with mice vaccinated with SPI2-proficient Salmonella, and this correlated with an increased amount of CD4+ as well as CD8+ T cells. Our study is the first example of interference of an intracellular bacterial pathogen with Ag presentation by DC. The subversion of DC functions is a novel strategy deployed by this pathogen to escape immune defense, colonize host organs, and persist in the infected host.

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Processing of viable Salmonella typhimurium for presentation of a CD4 T cell epitope from the Salmonella invasion protein C (SipC)

Cited by 27 publications

References 29 publications

The Toxoplasma gondii Peptide AS15 Elicits CD4 T Cells That Can Control Parasite Burden

The Toxoplasma gondii Peptide AS15 Elicits CD4 T Cells That Can Control Parasite Burden

Low-DoseSalmonellaInfection Evades Activation of Flagellin-Specific CD4 T Cells

Intracellular Salmonella Inhibit Antigen Presentation by Dendritic Cells

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