Gordon J. Freeman

Adhesion and Costimulatory Molecules

For successful immune activation, T-cells require two signals. The first signal confers specificity and is mediated by the T-cell receptor (TCR). The second signal, costimulation, is delivered by accessory cell-surface molecules expressed on antigenpresenting cells (APCs). In the absence of costimulation, T-cells enter a state of unresponsiveness termed anergy in vitro and tolerance in vivo (1,2). Anergy reflects the inability of antigen-specific T-cells stimulated through their antigen receptor to mount a secondary antigen-specific response on rechallenge. Tolerance is the identical response reflected in the inability of the intact host to mount an effective secondary antigen-specific response in vivo. Induction of anergy is a dynamic process during which T-cells remain alive yet unreactive toward antigens. T-cell tolerance is defined as the inability of an organism to distinguish foreign from self and can be the result of either deletion or inactivation of the antigen-specific T-cells. Tolerance in the thymus is largely a result of clonal deletion. However, recent studies have demonstrated that T-cell inactivation or anergy is a major mechanism of subsequent tolerance in the peripheral lymphoid tissue.