Dendritic Cells Induce Peripheral T Cell Unresponsiveness under Steady State Conditions in Vivo

TLDR

Dendritic cells can initiate immune responses but may also induce peripheral tolerance. The study aimed to investigate DC function in steady state by targeting them with a monoclonal antibody to the DEC‑205 receptor. They delivered antigen to DCs in vivo using a monoclonal antibody against the DC‑restricted endocytic receptor DEC‑205. Targeting antigens to DCs through DEC‑205 robustly activates T cells but, in the absence of co‑stimulation, the response wanes within a week and the cells become unresponsive, whereas co‑delivery with anti‑CD40 shifts the outcome to prolonged activation and immunity.

Abstract

Dendritic cells (DCs) have the capacity to initiate immune responses, but it has been postulated that they may also be involved in inducing peripheral tolerance. To examine the function of DCs in the steady state we devised an antigen delivery system targeting these specialized antigen presenting cells in vivo using a monoclonal antibody to a DC-restricted endocytic receptor, DEC-205. Our experiments show that this route of antigen delivery to DCs is several orders of magnitude more efficient than free peptide in complete Freund's adjuvant (CFA) in inducing T cell activation and cell division. However, T cells activated by antigen delivered to DCs are not polarized to produce T helper type 1 cytokine interferon gamma and the activation response is not sustained. Within 7 d the number of antigen-specific T cells is severely reduced, and the residual T cells become unresponsive to systemic challenge with antigen in CFA. Coinjection of the DC-targeted antigen and anti-CD40 agonistic antibody changes the outcome from tolerance to prolonged T cell activation and immunity. We conclude that in the absence of additional stimuli DCs induce transient antigen-specific T cell activation followed by T cell deletion and unresponsiveness.