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

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.

Keywords: 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.