The T-cell-receptor signaling network

T-cell-receptor (TCR) signaling in response to antigen recognition has a central role in the adaptive immune response. Furthermore, the comprehensive nature of the TCR signaling network is such that it has become a model system for complex cellular responses ranging from gene regulation to cytoskeletal remodeling. Over the past five years, our understanding of TCR signaling has evolved on a number of fronts. Tremendous progress has been made in the characterization of pathways that link early signaling events to downstream transcriptional responses. There has also been significant improvement in our understanding of how TCR signals regulate the cytoskeleton. Our knowledge of how other cell-surface receptors modulate TCR signaling and T-cell effector functions has also continued to advance. Finally, the cell-biological context within which TCR signaling takes place has emerged as a fascinating area of study. Here, I have schematized the core elements of the TCR signaling network in a series of panels, each of which encompasses one aspect of its function: early membrane-proximal signaling steps; the pathways that link TCR signaling to cytoskeletal reorganization; how early TCR signals are coupled to downstream pathways that alter gene expression; the costimulatory receptors of the CD28 family; and finally, how early TCR signaling is coupled to the formation of the immunological synapse – a stable and specialized junction between the T cell and the antigen-presenting cell (APC). For clarity, I have omitted a number of elements and connections from each of the panels. Early TCR signals The recognition of cognate antigenic peptide in the context of major histocompatibility complex (peptide-MHC) by the TCR is thought to induce conformational changes within the associated CD3 chains that facilitate their phosphorylation and association with downstream proteins (Alarcon et al., 2003). The CD3 δ-, γ-, ε- and ζ-chains all contain immunoreceptor tyrosine-based activation motifs (ITAMs), which are phosphorylated by the Src kinase leukocyte-specific tyrosine kinase (Lck