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CD4^–8^– Dendritic Cells Prime CD4⁺ T Regulatory 1 Cells to Suppress Antitumor Immunity¹

Xueshu Zhang^*, Hui Huang^*, Jinying Yuan^*, Deming Sun, Wu-Shiun Hou, John Gordon and Jim Xiang^2,*

^* Departments of Oncology, Microbiology, and Immunology and Department of Veterinary Microbiology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; Department of Ophthalmology and Visual Sciences, University of Louisville, Louisville, KY 40202; and Center for Cancer Research, Massachusetts Institute of Technology, Cambridge, MA 02139

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 (DC_OVA)) 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⁺ DC_OVA induced strong tumor-specific CD4⁺ Th1 responses and fully protective CD8⁺ CTL-mediated antitumor immunity, whereas CD4^–8^– DC_OVA, which were less mature and secreted substantial TGF- 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^– DC_OVA and IL-10^–/– OT II CD4⁺ T cells, into CD4^–8⁺ DC_OVA-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.

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