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Thirty different genes including cytokines, chemokines, granzymes, perforin and specifically integrins were evaluated in Peyer's patch-KdGag197-205-specific CD8+ T cells (pools of 100 cells) using Fluidigm 48.48 Dynamic arrays following three different prime-boost immunization strategies. Data revealed that the route of prime or the booster immunization differentially influenced the integrin expression profile on gut KdGag197-205-specific CD8+ T cells. Specifically, elevated numbers of integrin αE and αD expressing gut KdGag197-205-specific CD8+ T cells were detected following mucosal but not systemic priming. Also, αE/β7 and αD/β2 heterodimerization were more noticeable in an intranasal (i.n.)/i.n. vaccination setting compared to i.n./intramuscular (i.m) or i.m./i.m. vaccinations. Moreover, in all vaccine groups tested α4 appeared to heterodimerize more closely with β7 then β1. Also MIP-1β, RANTES, CCR5, perforin and integrin α4 bio-markers were significantly elevated in i.n./i.m. and i.m./i.m. immunization groups compared to purely mucosal i.n./i.n. delivery. Furthermore, when wild type (WT) BALB/c and IL-13 knockout (KO) mice were immunized using i.n./i.m. strategy, MIP-1α, MIP-1β, RANTES, integrins α4, β1 and β7 mRNA expression levels were found to be significantly different, in mucosal verses systemic KdGag197-205-specific CD8+ T cells. Interestingly, the numbers of gut KdGag197-205-specific CD8+ T cells expressing gut-homing markers α4β7 and CCR9 protein were also significantly elevated in IL-13 KO compared to WT control. Collectively, our findings further corroborate that the route of vaccine delivery, tissue microenvironment and IL-13 depleted cytokine milieu can significantly alter the antigen-specific CD8+ T cell gene expression profiles and in turn modulate their functional avidities as well as homing capabilities.

Sepsis is a systemic inflammatory response to infection and a leading cause of death. Mucosal-associated invariant T (MAIT) cells are innate-like T cells enriched in mucosal tissues that recognize bacterial ligands. We investigated MAIT cells during clinical and experimental sepsis, and their contribution to host responses. In experimental sepsis, MAIT-deficient mice had significantly increased mortality and bacterial load, and reduced tissue-specific cytokine responses. MAIT cells of WT mice expressed lower levels of IFN-g and IL-17a during sepsis compared to sham surgery, changes not seen in non-MAIT T cells. MAIT cells of patients at sepsis presentation were significantly reduced in frequency compared to healthy donors, and were more activated, with decreased IFN-g production, compared to both healthy donors and paired 90-day samples. Our data suggest that MAIT cells are highly activated and become dysfunctional during clinical sepsis, and contribute to tissue-specific cytokine responses that are protective against mortality during experimental sepsis. [ABSTRACT FROM AUTHOR]

Thirty genes composed of cytokines, chemokines, granzymes, perforin and integrins were evaluated in gut and splenic K d Gag 197–205 -specific single CD8 + T cells using Fluidigm 48.48 Dynamic arrays, with the aim of identifying biomarkers to predict effective mucosal and systemic vaccine efficacy. The mRNA expression profiles were analyzed in three ways: (i) the “number” of K d Gag 197–205 -specific CD8 + T cells expressing the biomarker, (ii) “level” of mRNA expression using principal component analysis (PCA) and (iii) poly-functionality in relation to RANTES expression. In total, 21 genes were found to be differentially expressed between the vaccine groups and the immune compartments tested. Overall, the PCA indicated that IL-13Rα2 or IL-4R antagonist adjuvanted vaccines that previously induced high-avidity mucosal/systemic CD8 + T cells with better protective efficacy, the “level” of mRNA expression, specifically RANTES, MIP-1β, and integrin α4 in gut K d Gag 197–205 -specific single CD8 + T cells, were significantly elevated compared to unadjuvanted vaccine. Furthermore, significantly elevated granzymes/perforin levels were detected in IL-13 −/− mice given the unadjuvanted vaccine, indicating that the degree of IL-13 inhibition (total, transient or no inhibition) can considerably alter the level of T-cell activity/poly-functionality. When splenic- and gut-K d Gag 197–205 -specific CD8 + T cells were compared, PC1 vs. PC2 scores revealed that not only RANTES, MIP-1β, and integrin α4 mRNA, but also perforin, granzymes A/B, and integrins β1 and β2 mRNA were elevated in spleen. Collectively, data suggest that RANTES, MIP-1β, perforin, and integrins α4, β1 and β7 mRNA in single HIV-specific CD8 + T cells could be used as a measure of effective mucosal and systemic vaccine efficacy. [ABSTRACT FROM AUTHOR]

Thirty different genes including cytokines, chemokines, granzymes, perforin and specifically integrins were evaluated in Peyer's patch-KdGag197–205-specific CD8+ T cells (pools of 100 cells) using Fluidigm 48.48 Dynamic arrays following three different prime-boost immunization strategies. Data revealed that the route of prime or the booster immunization differentially influenced the integrin expression profile on gut KdGag197–205-specific CD8+ T cells. Specifically, elevated numbers of integrin αE and αD expressing gut KdGag197–205-specific CD8+ T cells were detected following mucosal but not systemic priming. Also, αE/β7 and αD/β2 heterodimerization were more noticeable in an intranasal (i.n.)/i.n. vaccination setting compared to i.n./intramuscular (i.m) or i.m./i.m. vaccinations. Moreover, in all vaccine groups tested α4 appeared to heterodimerize more closely with β7 then β1. Also MIP-1β, RANTES, CCR5, perforin and integrin α4 bio-markers were significantly elevated in i.n./i.m. and i.m./i.m. immunization groups compared to purely mucosal i.n./i.n. delivery. Furthermore, when wild type (WT) BALB/c and IL-13 knockout (KO) mice were immunized using i.n./i.m. strategy, MIP-1α, MIP-1β, RANTES, integrins α4, β1 and β7 mRNA expression levels were found to be significantly different, in mucosal verses systemic KdGag197–205-specific CD8+ T cells. Interestingly, the numbers of gut KdGag197–205-specific CD8+ T cells expressing gut-homing markers α4β7 and CCR9 protein were also significantly elevated in IL-13 KO compared to WT control. Collectively, our findings further corroborate that the route of vaccine delivery, tissue microenvironment and IL-13 depleted cytokine milieu can significantly alter the antigen-specific CD8+ T cell gene expression profiles and in turn modulate their functional avidities as well as homing capabilities. [ABSTRACT FROM AUTHOR]

The roles of interleukin (IL)-4 and IL-13 during both innate and adaptive Th2 mediated immunity have received considerable scrutiny, however, mechanisms by which these cytokines influence the cellular interactions involved in negatively modulating the development of effective Th1 immunity are poorly characterized. In this article we discuss the recent advances in IL-4/IL-13 biology, mainly (i) role of these cytokines in allergic inflammation, atopic dermatitis, cancer, transplant rejection, bacterial/viral infections, and specifically the therapeutic potential of IL-13Rα2, (ii) insights into how “alarmin” stimulation activate IL-4/IL-13 at the lung mucosae, (iii) how these two cytokines modulate antigen-specific CD8 + T cell quality/avidity in a vaccine route dependent manner and (iv) finally discuss the potential of using transient inhibition of IL-4 and/or IL-13 at the vaccination site as a platform vaccine technology to induce strong sustained high quality CD8 + T cell immunity for protection against many chronic mucosal pathogens such as HIV-1. [ABSTRACT FROM AUTHOR]