In OVA-sensitized and challenged mice, γδ T cells expressing Vγ1 enhance airway hyperresponsiveness (AHR) but the underlying mechanism is unclear. These cells also reduce IL-10 levels in the airways, suggesting that they might function by inhibiting CD4+CD25+ regulatory T cells (Treg) or other CD4+ T cells capable of producing IL-10 and suppressing AHR. Indeed, sensitization and challenge with OVA combined with inactivation of Vγ1+ cells increased CD4+CD25+ cells in the lung, and markedly those capable of producing IL-10. The cellular change was associated with increased IL-10 and TGF-β levels in the airways, and a decrease of IL-13. Treg include naturally occurring Foxp3+ Treg, inducible Foxp3− Treg, and antigen-specific Treg many of which express folate receptor 4 (FR4). Although Foxp3 gene expression in the lung was also increased pulmonary CD4+ T cells, expressing Foxp3-protein or FR4 remained stable. Therefore, the inhibition by Vγ1+ γδ T cells might not be targeting Foxp3+ Treg but rather CD4+ T cells destined to produce IL-10.
The vaccinia virus TianTan (VTT) has been modified as an HIV vaccine vector in China and has shown excellent performance in immunogenicity and safety. However, its adverse effects in immunosuppressed individuals warrant the search for a safer vector in the following clinic trails. In this study, we deleted the C7L and K1L genes of VTT and constructed six recombinant vaccinia strains VTT△C7L, VTT△K1L, VTT△C7LK1L, VTKgpe△C7L, VTKgpe△K1L and VTT△C7LK1L-gag. The pathogenicity and immunogenicity of these recombinants were evaluated in mouse and rabbit models. Comparing to parental VTT, VTT△C7L and VTT△K1L showed significantly decreased replication capability in CEF, Vero, BHK-21 and HeLa cell lines. In particular, replication of VTT△C7LK1L decreased more than 10-fold in all four cell lines. The virulence of all these mutants were decreased in BALB/c mouse and rabbit models; VTT△C7LK1L once again showed the greatest attenuation, having resulted in no evident damage in mice and erythema of only 0.4 cm diameter in rabbits, compared to 1.48 cm for VTT. VTKgpe△C7L, VTKgpe△K1L and VTT△C7LK1L-gag elicited as strong cellular and humoral responses against HIV genes as did VTKgpe, while humoral immune response against the vaccinia itself was reduced by 4-8-fold. These data show that deletion of C7L and K1L genes leads to significantly decreased virulence without compromising animal host immunogenicity, and may thus be key to creating a more safe and effective HIV vaccine vector.
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