Low antigen dose in adjuvant-based vaccination selectively induces CD4 T cells with enhanced functional avidity and protective efficacy

Abstract

Abstract T cells of high functional avidity sense and respond to low levels of antigen (Ag), and their superior protective efficacy was first described using CD8 T cells cultured in vitro with low levels of Ag resulting in higher avidity and anti-tumor/viral efficacy compared to low avidity T cells cultured with high Ag concentrations. Selectively inducing high avidity by low Ag concentrations has required in vitro expansion so far, as in vivo attempts with low-dose vaccination gave no response. We show for the first time that functionally high avidity CD4, but not CD8, T cells are selectively primed in vivo by low concentrations of Ag in the strong crosspriming liposomal cationic adjuvant formulations (CAF) DDA/TDB or DDA/MMG/pIC from SSI. Increased functional avidity observed after low-dose vaccinations correlated with lower surface expression of PD-1 and higher per cell IFN-gamma production compared to low avidity CD4 T cells. We further show that IL-15, known to increase functional avidity of CTLs, is essential for high avidity of vaccine specific CD4 T cells. Importantly, high avidity CD4 T cells offered superior protection in a murine model of latent infection with Mycobacterium tuberculosis compared to low avidity T cells. Furthermore, adoptive transfers of HIV-IIIB gp140-specific CD4 T cells of high functional avidity resulting from low-dose immunizations in combination with TCR transgenic HIV-IIIB gp120 specific CTLs conferred superior protection against viral (vaccinia-HIV-IIB-gp140) challenge compared to TCR-Tg CTLs alone or in combination with low avidity CD4 T cells induced by high-dose immunization. Thus, inducing high avidity CD4 T cells by low-dose immunization is important in clearing viral and bacterial infections.