T cell costimulatory pathways in allograft rejection and tolerance: what's new?

The induction or maintenance of allograft tolerance remains an ongoing challenge. One approach to the development of tolerogenic strategies involves targeting T-cell costimulatory signals. The two most widely studied costimulatory pathways are the CD28/B7 and CD40/CD154 pathways, and blocking of both, either alone or in combination, has been shown to prolong allograft survival in rodents and primates. Recent work revealed that CD28-independent 'novel costimulatory' pathways exist, which can mediate allograft rejection. This review highlights new studies on the role of these pathways in allograft rejection and tolerance.

NK cells, CD8 T cells, and memory-effector responses appear to be less dependent on CD28 and/or CD154 costimulation, and utilize these novel costimulatory pathways for activation. The novel signals differ in their ability to enhance or inhibit T-cell activation, in their temporal and spatial expression patterns, and in their relative importance within the hierarchy of costimulatory signals. Emerging data suggest that costimulatory molecules are expressed on parenchymal cells.

A strategy to induce tolerance might involve targeting novel costimulatory signals particularly at the time point of maximal expression, and delivering negative signals, while inhibiting the positive signals that drive T-cell alloresponses.