T Cell Receptor Signaling: Beyond Complex Complexes

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The adaptive phase of the immune response begins with engagement on CD4 + helper T cells of the T cell antigen receptor (TCR) 1 by its ligand, a small foreign peptide bound to a cell surface protein of the class II major histocompatibility complex (peptide-MHC) expressed on an antigen-presenting cell. This engagement initiates a series of biochemical events that can differentially signal the naive T cell to: 1) enter into a pathway leading to generation of effector T cells with the onset of rapid proliferation and production of effector cytokines; 2) enter into a state of antigenic non-responsiveness known as anergy; or 3) die by apoptosis. The type of response elicited depends on multiple factors including the affinity of the interaction, the duration of the interaction, and the presence or absence of various costimulatory signaling inputs such as those provided by the CD4 coreceptor and the CD28 costimulatory receptor. In this review we provide an overview of the signaling events that are associated with the first of these outcomes: T cell activation. To present an overview of sufficiently broad scope, the depth of discussion of each aspect ofTCR signaling is by necessity limited, and the reader is referred to the reviews cited throughout this text for consideration of these events in more detail.