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Effector CD8+ T cells are generated in response to an immunodominant epitope in type III effector YopE during primary Yersinia pseudotuberculosis infection.

ABSTRACT: YopE is a virulence factor that is secreted into host cells infected by Yersinia species. The YopE C-terminal domain has GTPase-activating protein (GAP) activity. The YopE N-terminal domain contains an epitope that is an immunodominant CD8(+) T cell antigen during primary infection of C57BL/6 mice with Yersinia pseudotuberculosis. The characteristics of the CD8(+) T cells generated in response to the epitope, which comprises YopE amino acid residues 69 to 77 (YopE(69-77)), and the features of YopE that are important for antigenicity during primary infection, are unknown. Following intravenous infection of naïve C57BL/6 mice with a yopE GAP mutant (the R144A mutant), flow cytometry analysis of splenocytes by tetramer and intracellular cytokine staining over a time course showed that YopE69-77-specific CD8(+) T cells producing gamma interferon (IFN-?) and tumor necrosis factor alpha (TNF-?) were generated by day 7, with a peak at day 14. In addition, ?80% of YopE(69-77)-specific CD8(+) T cells were positive for KLRG1, a memory phenotype marker, at day 21. To determine if residues that regulate YopE activity by ubiquitination or membrane localization affect the antigenicity of YopE(69-77), mice were infected with a yopE ubiquitination or membrane localization mutant (the R62K or L55N I59N L63N mutant, respectively). These mutants elicited YopE(69-77)-specific CD8(+) T cells producing IFN-? and TNF-? with kinetics and magnitudes similar to those of the parental R144A strain, indicating that primary infection primes effector CD8(+) T cells independently of the ubiquitination or membrane localization of YopE. Additionally, at day 7, there was an unexpected positive correlation between the numbers of YopE(69-77)-specific CD8(+) T cells and CD11b(+) cells, but not between the numbers of YopE(69-77)-specific CD8(+) T cells and bacterial cells, in spleens, suggesting that the innate immune response contributes to the immunodominance of YopE(69-77).

SUBMITTER: Zhang Y

PROVIDER: S-EPMC4097610 | biostudies-literature | 2014 Jul

REPOSITORIES: biostudies-literature

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Effector CD8+ T cells are generated in response to an immunodominant epitope in type III effector YopE during primary Yersinia pseudotuberculosis infection.

Zhang Yue Y Mena Patricio P Romanov Galina G Bliska James B JB

Infection and immunity 20140505 7

YopE is a virulence factor that is secreted into host cells infected by Yersinia species. The YopE C-terminal domain has GTPase-activating protein (GAP) activity. The YopE N-terminal domain contains an epitope that is an immunodominant CD8(+) T cell antigen during primary infection of C57BL/6 mice with Yersinia pseudotuberculosis. The characteristics of the CD8(+) T cells generated in response to the epitope, which comprises YopE amino acid residues 69 to 77 (YopE(69-77)), and the features of Yo ...[more]

PMID: 24799630

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Project description:Specialized protein translocation systems are used by many bacterial pathogens to deliver effector proteins into host cells that interfere with normal cellular functions. How the host immune system recognizes and responds to this intrusive event is not understood. To address these questions, we determined the mammalian cellular response to the virulence-associated type III secretion system (T3SS) of the human pathogen Yersinia pseudotuberculosis. We found that macrophages devoid of Toll-like receptor (TLR) signaling regulate expression of 266 genes following recognition of the Y. pseudotuberculosis T3SS. This analysis revealed two temporally distinct responses that could be separated into activation of NFkappaB- and type I IFN-regulated genes. Extracellular bacteria were capable of triggering these signaling events, as inhibition of bacterial uptake had no effect on the ensuing innate immune response. The cytosolic peptidoglycan sensors Nod1 and Nod2 and the inflammasome component caspase-1 were not involved in NFkappaB activation following recognition of the Y. pseudotuberculosis T3SS. However, caspase-1 was required for secretion of the inflammatory cytokine IL-1beta in response to T3SS-positive Y. pseudotuberculosis. In order to characterize the bacterial requirements for induction of this novel TLR-, Nod1/2-, and caspase-1-independent response, we used Y. pseudotuberculosis strains lacking specific components of the T3SS. Formation of a functional T3SS pore was required, as bacteria expressing a secretion needle, but lacking the pore-forming proteins YopB or YopD, did not trigger these signaling events. However, nonspecific membrane disruption could not recapitulate the NFkappaB signaling triggered by Y. pseudotuberculosis expressing a functional T3SS pore. Although host cell recognition of the T3SS did not require known translocated substrates, the ensuing response could be modulated by effectors such as YopJ and YopT, as YopT amplified the response, while YopJ dampened it. Collectively, these data suggest that combined recognition of the T3SS pore and YopBD-mediated delivery of immune activating ligands into the host cytosol informs the host cell of pathogenic challenge. This leads to a unique, multifactorial response distinct from the canonical immune response to a bacterium lacking a T3SS.

Dataset Information

Effector CD8+ T cells are generated in response to an immunodominant epitope in type III effector YopE during primary Yersinia pseudotuberculosis infection.

Publications

Effector CD8+ T cells are generated in response to an immunodominant epitope in type III effector YopE during primary Yersinia pseudotuberculosis infection.

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