Systemic administration of antigen-loaded CD40-deficient dendritic cells mimics soluble antigen administration.

The decision to mount a T cell response to antigen (Ag) is dependent on the cellular context in which the Ag is presented. Activated dendritic cells (DC) are potent stimulators of immune responses, an ability which is linked to their high expression of several costimulatory molecules. In contrast, resting DC have been implicated in the generation of self tolerance, presumably due to their reduced costimulatory capacity. However, the precise molecular basis for the choice between Ag-induced immunity and unresponsiveness remains unclear. We show here that CD40 plays an important rolein this decision. Systemic administration of Ag-loaded, CD40-deficient DC failed to induce a productive primary T cell expansion and rendered mice relatively unresponsive to subsequent immunization with Ag in adjuvant. Using a TCR-transgenic T cell transfer system, we found that CD40(-/-) DC triggered an initial T cell activation that could not be sustained, resulting in loss of Ag-reactive T cells and reduced cytokine production by those T cells that did persist. Furthermore, administration of CD40(-/-) DC that had been loaded with a central nervous system autoantigen was found to protect mice from autoimmune pathology. These data implicate the CD40:CD40L interaction as a key checkpoint in the development of T cell immunity rather than tolerance.