Molecular Mechanisms in Allergy and Clinical Immunology
T-cell activation through the antigen receptor. Part 1: Signaling components, signaling pathways, and signal integration at the T-cell antigen receptor synapse,☆☆

https://doi.org/10.1067/mai.2002.124259Get rights and content

Abstract

Part 1 of this review will highlight the basic components and signaling pathways by which the T-cell antigen receptor (TCR) activates mature extrathymic T cells. TCR signaling commences with an early wave of protein tyrosine kinase activation, which is mediated by the Src kinases Lck and Fyn, the 70-kd ζ-associated protein kinase, and members of the Tec kinase family. This early wave of protein tyrosine phosphorylation leads to the activation of downstream signaling pathways, including an increase in intracellular free calcium, protein kinase C, nuclear factor κB and Ras-mitogen-activated protein kinase activation. These pathways activate transcription factors, such as activator protein 1, nuclear factor of activated T cells, and Rel proteins, which ultimately lead to the expression of genes that control cellular proliferation, differentiation, anergy, or apoptosis. This review also describes how costimulatory receptors assist in signal transduction and assembly of macromolecular complexes at the TCR contact site with the antigen-presenting cell, also known as the immune synapse. These basic concepts of TCR signal transduction will be used in part 2 to explain how T-cell function can be altered by therapeutic targeting of TCR signaling components, as well as to explain modification of TCR signaling during TH1/TH2 differentiation, tolerance, and immune senescence. (J Allergy Clin Immunol 2002;109:758-70.)

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.)

. Examples of key adapter proteins that play a role in TCR signaling. A shows the formation of a signaling complex that regulates IP turnover and [Ca2+]i flux. The

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.

References (100)

  • J Sloan-Lancaster et al.

    Partial T cell signaling: altered phospho-zeta and lack of Zap70 recruitment in APL-induced T cell anergy

    Cell

    (1994)
  • PE Love et al.

    ITAM multiplicity and thymocyte selection: how low can you go?

    Immunity

    (2000)
  • JA Nunes et al.

    Signal transduction by CD28 costimulatory receptor on T cells. B7-1 and B7-2 regulation of tyrosine kinase adaptor molecules

    J Biol Chem

    (1996)
  • TS Finco et al.

    LAT is required for TCR-mediated activation of PLCgamma1 and the Ras pathway

    Immunity

    (1998)
  • W Zhang et al.

    LAT palmitoylation: its essential role in membrane microdomain targeting and tyrosine phosphorylation during T cell activation

    Immunity

    (1998)
  • N Blomberg et al.

    The PH superfold: a structural scaffold for multiple functions

    Trends Biochem Sci

    (1999)
  • T Kurosaki et al.

    BLNK: connecting Syk and Btk to calcium signals

    Immunity

    (2000)
  • JM Penninger et al.

    The actin cytoskeleton and lymphocyte activation

    Cell

    (1999)
  • S Baksh et al.

    The role of calcineurin in lymphocyte activation

    Semin Immunol

    (2000)
  • SW Henning et al.

    GTPases in antigen receptor signalling

    Curr Opin Immunol

    (1998)
  • AE Nel et al.

    Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-gamma 1, and other phosphoproteins with Grb2 and the zeta-chain of the TCR

    J Biol Chem

    (1995)
  • S Gupta et al.

    The T-cell antigen receptor utilizes Lck, Raf-1, and MEK-1 for activating MAP kinase: evidence for the existence of a second PKC-dependent pathway in an Lck-negative Jurkat cell mutant

    J Biol Chem

    (1994)
  • J Jain et al.

    Transcriptional activation of the IL-2 gene

    Curr Opin Immunol

    (1995)
  • B Su et al.

    JNK is involved in signal integration during costimulation of T lymphocytes

    Cell

    (1994)
  • DD Yang et al.

    Differentiation of CD4+ T cells to Th1 cells requires MAP kinase JNK2

    Immunity

    (1998)
  • SG Ward et al.

    PI 3-kinase: a pivotal pathway in T-cell activation?

    Immunol Today

    (1996)
  • DR Alessi et al.

    Mechanism of activation and function of protein kinase B

    Curr Opin Genet Dev

    (1998)
  • CH Regnier et al.

    Identification and characterization of an IkappaB kinase

    Cell

    (1997)
  • EW Harhaj et al.

    IkappaB kinases serve as a target of CD28 signaling

    J Biol Chem

    (1998)
  • LH Boise et al.

    CD28 costimulation can promote T cell survival by enhancing the expression of Bcl-XL

    Immunity

    (1995)
  • M Villalba et al.

    A novel functional interaction between Vav and PKCtheta is required for TCR-induced T cell activation

    Immunity

    (2000)
  • W Sun et al.

    MEKK2 associates with the adapter protein Lad/RIBP and regulates the MEK5-BMK1/ERK5 pathway

    J Biol Chem

    (2001)
  • BC Schaefer et al.

    Live cell fluorescence imaging of T cell MEKK2: redistribution and activation in response to antigen stimulation of the T cell receptor

    Immunity

    (1999)
  • RH. Schwartz

    Costimulation of T lymphocytes: the role of CD28, CTLA-4, and B7/BB1 in interleukin-2 production and immunotherapy

    Cell

    (1992)
  • R Xavier et al.

    Membrane compartmentation and the response to antigen

    Curr Opin Immunol

    (1999)
  • JM Penninger et al.

    The actin cytoskeleton and lymphocyte activation

    Cell

    (1999)
  • R Rohatgi et al.

    The interaction between N-WASP and the Arp2/3 complex links Cdc42-dependent signals to actin assembly

    Cell

    (1999)
  • C Krawczyk et al.

    Molecular controls of antigen receptor clustering and autoimmunity

    Trends Cell Biol

    (2001)
  • A. Bretscher

    Regulation of cortical structure by the ezrin-radixin-moesin protein family

    Curr Opin Cell Biol

    (1999)
  • SF Pietromonaco et al.

    Protein kinase C-theta phosphorylation of moesin in the actin-binding sequence

    J Biol Chem

    (1998)
  • MM Davis et al.

    Ligand recognition by alpha beta T cell receptors

    Annu Rev Immunol

    (1998)
  • DR. Madden

    The three-dimensional structure of peptide-MHC complexes

    Annu Rev Immunol

    (1995)
  • DN Garboczi et al.

    Structure of the complex between human T-cell receptor, viral peptide and HLA-A2

    Nature

    (1996)
  • A Viola et al.

    T cell activation determined by T cell receptor number and tunable thresholds

    Science

    (1996)
  • DH Chu et al.

    The Syk family of protein tyrosine kinases in T-cell activation and development

    Immunol Rev

    (1998)
  • EM Schaeffer et al.

    Requirement for Tec kinases Rlk and Itk in T cell receptor signaling and immunity

    Science

    (1999)
  • O Acuto et al.

    T cell activation and the cytoskeleton

    Annu Rev Immunol

    (2000)
  • A Rao et al.

    Transcription factors of the NFAT family: regulation and function

    Annu Rev Immunol

    (1997)
  • CT Kuo et al.

    Transcriptional regulation of T lymphocyte development and function

    Annu Rev Immunol

    (1999)
  • ML Dustin et al.

    Costimulation: building an immunological synapse

    Science

    (1999)
  • Cited by (0)

    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).

    ☆☆

    Reprint requests: Andre Nel, MD, Division of Clinical Immunology/Allergy, UCLA School of Medicine, 10833 Le Conte Ave., Los Angeles, CA 90095-1680.

    View full text