Role of IL-17 in HIV-specific CD8+T cell immunity
Creators: name: Ravichandran, Jayashree
Publisher: name: The Australian National University
Year: 2012
Subjects: subject: Interleukins
subject: HIV infections Immunological aspects
subject: Cellular immunity
subject: T cells

description: It has been more than three decades since HIV (Human Immunodeficiency virus)1 has been identified as the causative agent of AIDS, but an effective vaccine is still underway. Various vaccine vector delivery systems have been developed to enhance CD8 T cell mediated immunity against HIV-1. In our laboratory, heterologous mucosal systemic HIV-1 poxvirus prime-boost immunization have shown to induce high avidity HIV-specific CD8 T cell with excellent protective immunity. These studies also revealed that mucosal immunization induced lower numbers of IL-4 and IL-13 expressing HIV-specific CD8 T cells compared to pure systemic delivery. Data indicated that the route of immunization can determine the quality or avidity of CD8 T cell immunity and this is mainly governed by Th2 cytokines IL-4 and IL-13. Th17 cells are a newly discovered subset of T cells that specifically produce cytokines IL-17A to F. Various studies have shown that both Th1 and Th2 cytokines negatively regulate IL-17A producing CD4 T cells in order to mediate their effector immune response. As Ranasinghe et al. have shown that IL-4 and IL-13 modulate the quality of CD8 T cells, this study aimed to establish whether the expression of IL-17A by HIV-specific CD8 T cells is dependent on Th2 cytokines IL-4, IL-13 or Th1 cytokine IFN-gamma. Wild type BALBc, IL-4, IL-13 and STAT6 KO mice were prime-boost immunized with control vaccine and the expression of IL-17A in spleen and lung were evaluated. Data indicated that the expression of IL-17A was significantly enhanced in HIV specific CD8 T cells obtained from all KO mice tested compared to WT BALBc control mice. But IFN-gamma did not have any effect on the IL-17A expression. To further investigate these findings and better understand the transcriptional regulation of IL-17A; wild type BALBc, IL-4, IL-13 and STAT6 KO mice were prime-boost immunized with control vaccine and RT-PCR was performed to evaluate the IL-17A regulatory factors in CD8 T cells following HIV-specific peptide stimulation. Data showed that IL-17A, TGF-beta, IL-6 and ROR-gamma t mRNA levels were highly elevated in CD8 T cells obtained from IL-4 KO mice compared to the other groups tested. This data further confirmed that IL-4 played a predominant role in down regulating IL-17A induction, and TGF-beta, IL-6 and ROR-gamma t (not IL-23a) were involved in this regulation. As previous studies in our laboratory have shown that IL-13 can significantly modulate the avidity of HIV-specific CD8 T cells, recently, Ranasinghe et al. have developed a vaccine that can temporarily inhibit IL-13 at the vaccination site. Since, IL-4 and IL-13 have shown to modulate IL-17A expression, in this study, the expression of IL-17A in HIV specific CD8 T cells was also evaluated using control vaccine and novel IL-13 inhibitor vaccine at 3 days, 14 days, 8 weeks and 10 days post-challenge. Data indicated that compared to the control vaccine, IL-13 inhibitor vaccine showed enhanced IL-17A expression by HIV-specific CD8 T cells at 14 days post booster vaccination and following surrogate influenza-HIV mucosal challenge in both spleen and lung. Collectively, the data indicate that out of the two Th2 cytokines, IL-4 mainly regulate the IL-7A expression in HIV-specific CD8 T cells. As IL-4 and IL-13 are involved in regulating the avidity of CTLs, data suggest that IL-17A plays an indirect role in modulating CD8 T cell avidity and protective immunity.