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The article focuses on the research on dendritic cells (DCs) showing that tolerance induced by resting DCs is dependent on engagement of the T cell inhibitory receptors PD-1 and CTLA-4. DCs are the principal cell type that display peptide antigens for the initiation of adaptive immune responses involving T cells and are also capable of shutting lymphocytes off, thus inducing tolerance in T cells. It remains unclear why resting DCs might preferentially engage inhibitory receptors of T cells. One hypothesis is that this phenomenon is related to the expression of costimulatory ligands and the affinities of activating versus inhibitory receptors for these ligands. A different but not mutually exclusive mechanism is that inhibition simply reflects a change in the activation threshold of T cells.

The authors reflect on the biology, therapeutic potential and challenges of T-cell costimulation. They say that T-cells are key mediators of the immune response, and their activation is tightly regulated to prevent autoreactivity. They add that the significant role of costimulation in regulating T-cell activation versus tolerance has stimulated great interest in the manipulation of costimulatory signals to either boost immune responses or induce tolerance.