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Discordant rearrangement of primary and anamnestic CD8+ T cell responses to influenza A viral epitopes upon exposure to bacterial superantigens: Implications for prophylactic vaccination, heterosubtypic immunity and superinfections.

ABSTRACT: Infection with (SAg)-producing bacteria may precede or follow infection with or vaccination against influenza A viruses (IAVs). However, how SAgs alter the breadth of IAV-specific CD8+ T cell (TCD8) responses is unknown. Moreover, whether recall responses mediating heterosubtypic immunity to IAVs are manipulated by SAgs remains unexplored. We employed wild-type (WT) and mutant bacterial SAgs, SAg-sufficient/deficient Staphylococcus aureus strains, and WT, mouse-adapted and reassortant IAV strains in multiple in vivo settings to address the above questions. Contrary to the popular view that SAgs delete or anergize T cells, systemic administration of staphylococcal enterotoxin B (SEB) or Mycoplasma arthritidis mitogen before intraperitoneal IAV immunization enlarged the clonal size of 'select' IAV-specific TCD8 and reshuffled the hierarchical pattern of primary TCD8 responses. This was mechanistically linked to the TCR V? makeup of the impacted clones rather than their immunodominance status. Importantly, SAg-expanded TCD8 retained their IFN-? production and cognate cytolytic capacities. The enhancing effect of SEB on immunodominant TCD8 was also evident in primary responses to vaccination with heat-inactivated and live attenuated IAV strains administered intramuscularly and intranasally, respectively. Interestingly, in prime-boost immunization settings, the outcome of SEB administration depended strictly upon the time point at which this SAg was introduced. Accordingly, SEB injection before priming raised CD127highKLRG1low memory precursor frequencies and augmented the anamnestic responses of SEB-binding TCD8. By comparison, introducing SEB before boosting diminished recall responses to IAV-derived epitopes drastically and indiscriminately. This was accompanied by lower Ki67 and higher Fas, LAG-3 and PD-1 levels consistent with a pro-apoptotic and/or exhausted phenotype. Therefore, SAgs can have contrasting impacts on anti-IAV immunity depending on the naïve/memory status and the TCR composition of exposed TCD8. Finally, local administration of SEB or infection with SEB-producing S. aureus enhanced pulmonary TCD8 responses to IAV. Our findings have clear implications for superinfections and prophylactic vaccination.

SUBMITTER: Meilleur CE

PROVIDER: S-EPMC7239382 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Discordant rearrangement of primary and anamnestic CD8+ T cell responses to influenza A viral epitopes upon exposure to bacterial superantigens: Implications for prophylactic vaccination, heterosubtypic immunity and superinfections.

Meilleur Courtney E CE Memarnejadian Arash A Shivji Adil N AN Benoit Jenna M JM Tuffs Stephen W SW Mele Tina S TS Singh Bhagirath B Dikeakos Jimmy D JD Topham David J DJ Mu Hong-Hua HH Bennink Jack R JR McCormick John K JK Haeryfar S M Mansour SMM

PLoS pathogens 20200520 5

Infection with (SAg)-producing bacteria may precede or follow infection with or vaccination against influenza A viruses (IAVs). However, how SAgs alter the breadth of IAV-specific CD8+ T cell (TCD8) responses is unknown. Moreover, whether recall responses mediating heterosubtypic immunity to IAVs are manipulated by SAgs remains unexplored. We employed wild-type (WT) and mutant bacterial SAgs, SAg-sufficient/deficient Staphylococcus aureus strains, and WT, mouse-adapted and reassortant IAV strain ...[more]

PMID: 32433711

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Project description:Staphylococcus aureus and Streptococcus pyogenes are significant human pathogens, causing infections at multiple body sites, including across the skin. Both are organisms that cause human diseases and secrete superantigens, including toxic shock syndrome toxin-1 (TSST-1), staphylococcal enterotoxins (SEs), and streptococcal pyrogenic exotoxins (SPEs). On the skin, human keratinocytes represent the first cell type to encounter these superantigens. We employed transcriptome sequencing (RNA-seq) to evaluate the human primary keratinocyte response to both TSST-1 and staphylococcal enterotoxin B (SEB) in triplicate analyses. Both superantigens caused large numbers of genes to be up- and downregulated. The genes that exhibited 2-fold differential gene expression compared to vehicle-treated cells, whether up- or downregulated, totaled 5,773 for TSST-1 and 4,320 for SEB. Of these, 4,482 were significantly upregulated by exposure of keratinocytes to TSST-1, whereas 1,291 were downregulated. For SEB, expression levels of 3,785 genes were upregulated, whereas those of 535 were downregulated. There was the expected high overlap in both upregulation (3,412 genes) and downregulation (400 genes). Significantly upregulated genes included those associated with chemokine production, with the possibility of stimulation of inflammation. We also tested an immortalized human keratinocyte line, from a different donor, for chemokine response to four superantigens. TSST-1 and SEB caused production of interleukin-8 (IL-8), MIP-3α, and IL-33. SPEA and SPEC were evaluated for stimulation of expression of IL-8 as a representative chemokine; both stimulated production of IL-8.IMPORTANCEStaphylococcus aureus and Streptococcus pyogenes are common human pathogens, causing infections that include the skin. Both pathogens produce a family of secreted toxins called superantigens, which have been shown to be important in human diseases. The first cell types encountered by superantigens on skin are keratinocytes. Our studies demonstrated, that the human keratinocyte pathway, among other pathways, responds to superantigens with production of chemokines, setting off inflammation. This inflammatory response may be harmful, facilitating opening of the skin barrier.

Dataset Information

Discordant rearrangement of primary and anamnestic CD8+ T cell responses to influenza A viral epitopes upon exposure to bacterial superantigens: Implications for prophylactic vaccination, heterosubtypic immunity and superinfections.

Publications

Discordant rearrangement of primary and anamnestic CD8+ T cell responses to influenza A viral epitopes upon exposure to bacterial superantigens: Implications for prophylactic vaccination, heterosubtypic immunity and superinfections.

Similar Datasets

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