Under normal conditions, NK cells circulate in blood but are largely excluded

from lymph nodes. However, by using a mouse model, Sallusto check details and colleagues clearly demonstrated that circulating NK cells were selectively recruited to lymph nodes after stimulation by some, but not all, injected matured DCs in a CXCR3-dependent manner and that these NK cells provide an early source of IFN-γ that is mandatory for subsequent Th1 polarization [18]. These authors concluded that for vaccines that rely on Th1 responses, vaccine adjuvants should be selected according to their capacity to induce the recruitment of NK cells in antigen-stimulated lymph nodes. The findings in the present study are consistent with recently published data Venetoclax nmr from our group where mature αDC1s, from healthy blood donors, efficiently recruited NK cells in a CXCL9-dependent manner [16]. In that study, αDC1s were also able to induce IFN-γ production when co-cultured with resting autologous NK cells, but only if CD40 ligation was provided. As NKT cells express a similar chemokine receptor profile as NK cells [19], CD40 ligands could possibly be provided by co-recruited CD1d-restricted NKT cells which

are known to upregulate CD40L when recognizing endogenous glycolipids presented on mature DCs [26]. The polarization of naïve CD4+ T cells towards Th1 is highly dependent on IL-12 produced by mature DCs after re-stimulation with CD40 ligands [27, 28]. IFN-γ has been described to support such IL-12-dependent Th1 polarization by increasing the ability of mature DCs both to produce IL-12 upon re-stimulation with CD40-ligands [29] and to support TCR-mediated expression of the IL-12 receptor in naïve T cells [30]. Further, to induce an efficient Th1-polarized antitumour response, a vaccine DC must also efficiently induce rare tumour-specific naïve

CD8+ T cells to become CTLs. Indeed, we also found that αDC1s had a higher production of CD8+ T cell-recruiting chemokines CCL3/MIP-1α and CCL4/MIP-1β upon CD40 ligation. Interestingly, findings in mice from Germain for and colleagues indicate that after immunization but before antigen recognition, naive CD8+ T cells in vaccine-draining lymph nodes upregulate the chemokine receptor CCR5 [20]. This upregulation permits these cells to be attracted to sites of antigen-specific DC–CD4+ T cell interaction where the chemokines CCL3/MIP-1α and CCL4/MIP-1β are produced. Importantly, interference with this actively guided recruitment reduced the ability of CD4+ T cells to promote memory CD8+ T cell generation, which indicates that these chemokines are of high importance for the immune system to optimally activate rare antigen-specific CD8+ cells.