T Cell Receptor Signaling: Beyond Complex Complexes

Yanping Huang,Ronald L Wange

doi:10.1074/jbc.r400012200

Yanping Huang, Ronald L Wange

Open Access

https://doi.org/10.1074/jbc.r400012200

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Abstract

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.

Highlights

TCR Structure The TCR is composed of six different polypeptide chains
Given the primacy of immunoreceptor tyrosine-based activation motifs (ITAMs) phosphorylation by Lck in TCR signaling, an especially important question to answer is how is ITAM tyrosine phosphorylation maintained below the signaling threshold prior to TCR engagement
The CD3 ITAMs are maintained in a subcritical state of tyrosine phosphorylation by tyrosine phosphatases, which have ready access to the TCR prior to TCR stimulation but more limited access following TCR stimulation [6, 7]

Summary

Cytoskeletal Reorganization and Formation of Immunological Synapse

A new layer of complexity in the process of TCR signaling has come to light in recent years in the form of the immunological synapse (IS), which has been referred to as the supramolecular activation complex (SMAC). This is a dynamic yet highly ordered structure that forms at the site of T cell contact with an antigenpresenting cell [19]. Clustering of lipid rafts at the contact site and formation of the IS is an active process that requires several upstream signaling events to occur Most important of these are the signals that lead to reorganization of the actin cytoskeleton. Itk plays a critical role in this process, apparently at the level of supporting Vav-1 recruitment to the plasma membrane [25, 26]

Activation of Transcription Factors

Concluding Remarks