Invariant NKT Cells Preferentially Modulate the Function of CD8α+ Dendritic Cell Subset in Inducing Type 1 Immunity against Infection

Abstract

Although studies suggest that NKT cell (NKT) activation modulates the function of dendritic cells (DCs) in inducing T cell responses, it is unknown whether this modulating effect is biased to a DC subset. We previously reported that NKT activation could modulate DC function in inducing protective T cell immunity to Chlamydia pneumoniae, an intracellular bacterial infection. In this study, we investigated the effect of NKT activation on DC subsets, using multiple approaches, including gene knockout mice, α- galactosylceramide stimulation, adoptive transfer of invariant NKT (iNKT), and functional analysis of DC subsets in both in vitro and in vivo settings. We found a preferential modulating effect of iNKTs on the CD8α+ DC subset. Specifically, we found that iNKT-deficient mice, compared with wild-type (WT) mice, showed reduced CD8α+ DC expansion with lower CD40 expression and IL-12 production, whereas enhancing iNKT activation in WT mice or adoptive transfer of iNKTs to Jα18−/− mice resulted in increased function of CD8α+ DCs in inducing type 1 immune responses. Further, DC-iNKT coculture experiments showed a direct CD40L-dependent enhancing effect of iNKTs on IL-12p70 production by CD8α+ DCs. More importantly, CD8α+ DCs from Jα18−/− mice, compared with those from WT mice, showed significantly reduced ability to activate IFN-γ–producing T cells in vitro and to induce type 1 immunity and protection in vivo. Moreover, a similar CD8α+ DC subset alteration was found in the Jα18−/− mice following Leishmania major infection. Our data provide the first direct evidence that iNKTs preferentially promote the functional development of a subset of DC to generate protective immunity against infections.