CTLA-4 — The Costimulatory Molecule That Doesn't: Regulation of T-cell Responses by Inhibition (original) (raw)

  1. C.A. CHAMBERS and
  2. J.P. ALLISON
  3. Howard Hughes Research Institute, Division of Immunology, Department of Molecular and Cellular Biology, University of California, Berkeley, California 94720

Excerpt

An effective immune response requires the activationand expansion of antigen-specific T cells and the generation of effector and memory T-cell populations. OptimalT-cell activation requires the interaction of the T-cellantigen receptor (TCR) with the appropriate antigen inthe context of self-major histocompatibility complex(MHC) molecules and a second signal termed costimulation. Recent elucidation of the X-ray crystal of the TCRand its specific MHC/peptide ligand has provided amolecular understanding of how T cells recognize foreign antigenic peptides in the context of MHC molecules.The regulation of how and whether a T cell with a particular clonal TCR will become activated once the TCR isengaged and whether it will become an efficient effectoror memory T cell, however, remains unclear. The availability of costimulation is one important factor in determining whether or not a T cell will become activated.Costimulation can regulate T-cell activation by (1) facilitating effective T-cell activation upon TCR engagement,particularly when specific antigens are present at lowconcentrations; (2) shaping the TCR repertoire of the responding T cells by enabling T cells expressing TCRswith a broad range of affinities to become activated; (3)providing an important mechanism for preventing nonspecific T-cell activation. Since costimulation in vivo isprobably provided in cis, restriction of costimulatory ligand expression to "professional" antigen-presentingcells (APCs) provides a mechanism for maintaining peripheral T-cell tolerance to tissue-specific antigens oncells that do not express these ligands (for review, seeMueller et al. 1989)...