Molecular Mechanisms in Allergy and Clinical ImmunologyT-cell activation through the antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse☆,☆☆
Section snippets
Initial phase of tyrosine protein kinase activation, including phosphorylation of immunoreceptor tyrosine-based activation motifs
The earliest recognizable event after TCR engagement by antigen is the induction of tyrosine protein phosphorylation by the Src kinases Lck and Fyn (Fig 1).2, 8, 9 How exactly these Src kinases are activated is unclear, but it involves maintenance of an activation-competent state by the removal of inhibitory C-terminal tyrosine phosphate residues by members of the CD45 tyrosine phosphatase family (Fig 1, A ).16 To do so, CD45 participates in the formation of multimeric complexes with the CD4
Costimulatory receptors affect early PTK activation
In addition to their role in stabilizing TCR interactions with the MHC, CD8 and CD4 play an active role in initiating PTK activity.16 Although it was originally thought that these Lck-binding coreceptors chaperone the kinase to the ITAMs, more recent data suggest that CD4 and CD8 may actually interact with the MHC after TCR binding to the peptide-MHC complex (Fig 1).17, 32 One explanation is that interaction of the Lck-SH2 motif with the ZAP-70 pY319 residue redirects CD4 or CD8 receptors to
Activation of signaling cascades downstream of the PTK cascade
The early wave of PTK activity leads to the recruitment, rearrangement, and activation of additional signaling molecules at the TCR contact site with antigen.11 The ITAMs, as well as the adapter proteins, play a key role in the assembly of post-TCR signaling complexes. (For a discussion of adapter molecules, see Box 2 and Fig 4.)
Dynamic integration of signals by the TCR synapse: role of lipid rafts, cytoskeleton, and supramolecular activation clusters
Although a considerable amount of information on TCR signaling has been obtained through the use of antibodies that ligate TCR or CD3, in vivo TCR activation require a contribution by APCs and accessory receptors, which introduces an additional level of complexity. This includes the requirement that the TCR and accessory receptors be assembled in the immunologic synapse (Fig 2). This contact site also serves as an assembly site for signaling molecules on the inner leaflet of the T-cell
Summary
All considered, TCR signaling is a dynamic event that can elicit a variety of T-cell responses, depending on the cellular subset and the conditions under which the TCR is engaged by the specific MHC-peptide ligand. Whether the cell responds to delivery of the TCR signal by proliferation, differentiation, apoptosis, anergy, development of memory, or cytotoxic killing depends on the quality of the TCR signal, as well as a host of modifying factors, such as cellular subset, costimulatory
Acknowledgements
I thank Mr Boyd Jacobson, manager of the Illustration Department, National Jewish Medical Center, for skillful design of the artwork, and Mr Photi Christofas for skillful assistance in preparing the manuscript. Because of space constraints, it was not possible to site the seminal contributions from a large number of investigators to this field.
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Cited by (0)
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Supported by a United States Public Health Service grant (RO-1 AG14992) and a grant from the UCLA Asthma, Allergy, and Immunologic Disease Center (PO-1 AI50495).
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Reprint requests: Andre Nel, MD, Division of Clinical Immunology/Allergy, UCLA School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095-1680.