Initiating protective T cell immunity by targeting antigens directly to maturing dendritic cells in lymphoid tissues

Abstract To initiate immunity, dendritic cells (DCs) must capture antigens and respond to additional stimuli that induce their differentiation or maturation. Maturation allows DCs to switch from their steady state function of tolerance to the induction of different types of immune responses, such as the formation of effector T cells and memory. To understand the control of immunity, particularly protective immunity, and to better harness immunology during vaccine design, we directly targeted antigens to DCs in vivo and manipulated their state of maturation. For tumors, we studied irradiated plasmacytoma cells, which best target DCs when the tumor cells are injected i.v. rather than s.c. The CD8 + CD205 + splenic DC subset selectively took up fragments of the tumor cells. When the CD1d binding glycolipid, α-galactosyl ceramide, was injected together with the tumor cells to engage NKT lymphocytes, DCs displayed many of the cardinal features of maturation. In particular, mice developed protective immunity that was long lived (> 2 months after a single vaccination), specific for J558 and not for other tumors, and required both CD4 + and CD8 + T cells. In the case of immunity to defined antigens, we engineered proteins into monoclonal antibodies that targeted to DCs in vivo. Following initial proof of concept studies to elicit protective immunity with ovalbumin as a model antigen, we inserted the HIV gag p24 protein in frame at the C-terminus of the heavy chain of antibodies to DEC-205 (anti-DEC-p24), an abundant endocytic receptor on DCs in lymphoid tissues. Targeting of antigens with this anti-DC monoclonal antibody increased the efficiency of immunization ∼100 fold relative to non-targeted p24 protein. Administration of anti-DEC-p24 with a maturation stimulus produced strong CD4 + T cell immunity to six different immunogenic peptides in three separate MHC backgrounds. Immunity was associated with protection against challenge with recombinant vaccinia gag at an airway surface. We propose that significant improvements in vaccine efficacy can be obtained by controlling two fundamental principles of immune function, i.e., antigen uptake by DCs and control of DC maturation.