IL-4 and IL-13 mediated down-regulation of CD8 expression levels can dampen anti-viral CD8⁺ T cell avidity following HIV-1 recombinant pox viral vaccination
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Wijesundara, Danushka K
Jackson, Ronald J
Tscharke, David C
Ranasinghe, Charani
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Elsevier
Abstract
We have shown that mucosal HIV-1 recombinant pox viral vaccination can induce high, avidity HIV-specific CD8(+) T cells with reduced interleukin (IL)-4 and IL-13 expression compared to, systemic vaccine delivery. In the current study how these cytokines act to regulate anti-viral CD8(+) T, cell avidity following HIV-1 recombinant pox viral prime-boost vaccination was investigated. Out of a panel of T cell avidity markers tested, only CD8 expression levels were found to be enhanced on, KdGag197-205 (HIV)-specific CD8(+) T cells obtained from IL-13(-/-), IL-4(-/-) and signal transducer and, activator of transcription of 6 (STAT6)(-/-) mice compared to wild-type (WT) controls following, vaccination. Elevated CD8 expression levels in this instance also correlated with polyfunctionality, (interferon (IFN)-γ, tumour necorsis factor (TNF)-α and IL-2 production) and the avidity of HIVspecific CD8(+) T cells. Furthermore, mucosal vaccination and vaccination with the novel adjuvanted IL-13 inhibitor (i.e. IL-13Rα2) vaccines significantly enhanced CD8 expression levels on HIV-specific CD8(+), T cells, which correlated with avidity. Using anti-CD8 antibodies that blocked CD8 availability on CD8(+), T cells, it was established that CD8 played an important role in increasing HIV-specific CD8(+) T cell avidity and polyfunctionality in IL-4(-/-), IL-13(-/-) and STAT6(-/-) mice compared to WT controls, following vaccination. Collectively, our data demonstrate that IL-4 and IL-13 dampen CD8 expression levels on anti-viral CD8(+) T cells, which can down-regulate anti-viral CD8(+) T cell avidity and, polyfunctionality following HIV-1 recombinant pox viral vaccination. These findings can be exploited to, design more efficacious vaccines not only against HIV-1, but many chronic infections where high, avidity CD8(+) T cells help protection.
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ANOVA, BD, Beckton Dickinson, CD8 expression, CD8(+) T cell avidity/polyfunctionality, FCS, FPV-HIV, FPV-HIV or VV-HIV encoding murine soluble IL-13Rα2, HIV-1 vaccines/vaccination, ICS, IFN, IFN-I, IL, IL-13 inhibitor vaccines, IL-13 receptor α 2, IL-13Rα2, IL-4/IL-13, LCMV, MFI, Mucosal vaccination, PBS, RBC, SEM, STAT6, T cell receptor, TCR, TNF, VV-HIV, VV-WR, WT, analysis of variance, fetal calf serum, fowlpox virus encoding HIV-1 antigens, i.m., i.n., i.p., interferon, interleukin, intracellular cytokine stain, intramuscular, intranasal, intraperitoneal, lymphocytic choriomeningitis virus, mean fluorescent intensity, pMHC-I, peptide-major histocompatibility class I complexes, phosphate buffer saline, red blood cell, signal transducer and activator of transcription 6, standard error of the mean, tumor necrosis factor, type I interferons, vaccinia virus Western Reserve strain, vaccinia virus encoding HIV-1 antigens, wild-type, AIDS Vaccines, Administration, Mucosal, Animals, Antigens, CD8, CD8-Positive T-Lymphocytes, Down-Regulation, Female, HIV-1, Interleukin-13, Interleukin-4, Mice, Mice, Inbred BALB C, Mice, Knockout, Vaccines, Synthetic
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Vaccine