The 'two signal' model of immune tolerance states that the deciding factor in the immunological outcome is the stage of dendritic cell (DC) maturation. Immature DCs can only deliver one signal (which results in tolerance) to the CD8+ T cells, whereas mature DCs can deliver two. But, in October 9 online Nature Immunology, Matthew Albert and colleagues, from Rockefeller University, New York show that the critical checkpoint for peripheral T cell tolerance is not DC maturation, but instead the presence of a third signal which is active at the DC-CD4+ T cell interface.

Albert et al. used a novel in vitro system to study cross-tolerance and found that dendritic cells phagocytose apoptotic cells and tolerize antigen-specific CD8+ T cells in the absence of similar CD4+ T helper cells. Using this system, they tested the 'two-signal' hypothesis for the regulation of priming versus tolerance...

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