Costimulatory pathways of T-cell activation

T lymphocytes play an essential role in the defense against several pathogens and in tumor immune surveillance. However, T cells can also trigger autoimmune diseases and acute allograft rejection. Therefore, understanding the mechanisms of activation of T lymphocytes may help develop novel immunomodulators for therapeutic purposes. T-cell activation results from recognition by the T-cell receptor of a specific antigenic peptide within a specific major histocompatibility complex molecule expressed on antigen-presenting cells (APCs). In addition, naı̈ve T cells express the costimulatory receptor CD28 that binds ligands also expressed on APCs. Coengagement of at least T-cell receptor and CD28 is necessary for naı̈ve T cells to undergo activation, proliferation, and differentiation. Upon activation, T cells transiently up-regulate a number of alternative costimulatory receptors [1]. In addition, recently activated T cells also express inhibitory receptors such as CTLA-4 [2], PD-1, BTLA, and Fas, the engagement of which may lead to cell-cycle arrest or apoptosis and limits the magnitude and/or duration of an immune response. Mice carrying null mutations of these inhibitory genes all develop different degrees of lymphoaccumulation and autoimmunity. The ratio of surface versus intracellular expression of CTLA-4, which determines how much CTLA-4 can bind its ligand, is regulated by the phosphorylation status of a tyrosine in its cytoplasmic tail [3–5]. Functionally, CTLA4 appears to regulate the threshold of T-cell activation, as CTLA-4–deficient T cells require lower levels of antigenic stimulation than CTLA-4 expressing T cells [6]. In addition, the inhibitory effect of CTLA-4 appears to be greater in secondary than in primary stimulation of naı̈ve T cells [6]. We have used several approaches centered on CTLA-4 to inhibit immune responses in vivo. First, targeted cross-linking of CTLA-4 using membranebound single-chain anti-CTLA-4 antibody expressed on