CD4−8− Dendritic Cells Prime CD4+ T Regulatory 1 Cells to Suppress Antitumor Immunity

It is clear that dendritic cells (DCs) are essential for priming of T cell responses against tumors. However, the distinct roles DC subsets play in regulation of T cell responses in vivo are largely undefined. In this study, we investigated the capacity of OVA-presenting CD4−8−, CD4+8−, or CD4−8+ DCs (OVA-pulsed DC (DCOVA)) in stimulation of OVA-specific T cell responses. Our data show that each DC subset stimulated proliferation of allogeneic and autologous OVA-specific CD4+ and CD8+ T cells in vitro, but that the CD4−8− DCs did so only weakly. Both CD4+8− and CD4−8+ DCOVA induced strong tumor-specific CD4+ Th1 responses and fully protective CD8+ CTL-mediated antitumor immunity, whereas CD4−8− DCOVA, which were less mature and secreted substantial TGF-β upon coculture with TCR-transgenic OT II CD4+ T cells, induced the development of IL-10-secreting CD4+ T regulatory 1 (Tr1) cells. Transfer of these Tr1 cells, but not T cells from cocultures of CD4−8− DCOVA and IL-10−/− OT II CD4+ T cells, into CD4−8+ DCOVA-immunized animals abrogated otherwise inevitable development of antitumor immunity. Taken together, CD4−8− DCs stimulate development of IL-10-secreting CD4+ Tr1 cells that mediated immune suppression, whereas both CD4+8− and CD4−8+ DCs effectively primed animals for protective CD8+ CTL-mediated antitumor immunity.