Key Points
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CD28 potently enhances T-cell receptor (TCR)-induced proliferation and differentiation of naive T cells, especially at low TCR occupancy, making it responsible for the signal two predicted by the two-signal hypothesis of lymphocyte activation.
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CD28 is a homodimer expressed by most mouse T cells, 90% of human CD4+ T cells and 50% of human CD8+ T cells. CD28 interacts with the two structurally homologous ligands — B7.1 (CD80) and B7.2 (CD86), expressed by activated antigen-presenting cells (APCs), such as dendritic cells.
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CD28-deficient mice have reduced responses to infectious pathogens, allograft antigens, graft-versus-host disease, contact hypersensitivity and asthma.
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Ligation of CD28 accelerates cell-cycle progression by enhancing the expression of D-cyclins, the activation of cyclin-dependent kinases and phosphorylation of the retinoblastoma family of proteins. CD28 favours T-cell survival by inducing nuclear factor-κB (NF-κB)-dependent expression of the anti-apoptotic protein BCL-XL and the development of T helper 2 (TH2) cells by promoting the expression of a 'second wave' of co-stimulatory receptors (such as CD40 ligand, OX40 and inducible co-stimulatory molecule (ICOS)
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Ligation of CD28 triggers the activation of the SRC-family protein tyrosine kinases (PTKs) LCK and FYN, phosphatidylinositide-3-kinase, the guanosine exchange factor VAV1 and TEC PTKs.
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CD28 amplifies membrane-proximal signalling that is generated by TCR ligation. TCR stimulation generates the central scaffolding (that is, the adaptors linker for activated T cells (LAT) and SH2-domain-containing leukocyte protein of 76 kDa (SLP76) on which CD28-activated signalling elements might dock for sustaining activation. One effect of CD28 co-stimulation is to reinforce actin-cytoskeleton rearrangement, which drives lipid-raft coalescence, TCR clustering and integrin activation.
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A support to a quantitative view of co-stimulation comes from microarray analysis showing that TCR-induced expression of many genes in primary T cells is amplified (or suppressed) to varying degrees by CD28 co-stimulation but no new gene is induced by CD28 co-ligation.
Abstract
The ability of naive T cells to clonally expand and acquire effector functions depends on the strength of signals received by the T-cell receptor (TCR) and by an array of co-stimulatory receptors — the most prominent of which is CD28. In this review, we discuss recent genetic, biochemical and biophysical data that indicate a modified view of the molecular mechanism by which ligation of CD28 amplifies TCR-mediated T-cell activation. These studies indicate that the commonly held notion of a qualitative signalling role of CD28 in T-cell activation should be revised.
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Acknowledgements
We thank P. Schwartzberg, R. Sen, F. Shannon and members of the Molecular Immunology Unit for discussions and suggestions, and W. Houssin for secretarial assistance. We thank the Pasteur Institute, the Association pour la Recherche sur le Cancer and the Centre National de la Recherche Scientifique for continuous grant support. Due to space restrictions, we apologize if we have omitted to cite any references.
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Glossary
- TWO-SIGNAL HYPOTHESIS
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The two-signal hypothesis was proposed as a mechanism to explain how lymphocyte stimulation by antigen induces an immune response or unresponsiveness. Briefly, the signal delivered by the antigen receptor alone could promote tolerance whereas development of an immune response requires a 'second signal' from a soluble or membrane-bound co-stimulatory factor.
- IMMUNORECEPTOR TYROSINE-BASED ACTIVATION MOTIFS
-
(ITAMs). Structural motifs that contain tyrosine residues, found in the cytoplasmic tails of several signalling molecules. The tyrosine residue in the Tyr-Xaa-Xaa-Leu/Ile motif is a target for phosphorylation by SRC kinases and subsequent binding of SH2-domain-containing proteins such as ZAP70 and SYK.
- GLYCOLIPID-ENRICHED MEMBRANE MICRODOMAINS
-
(GEMs). Cholesterol-rich dynamic microdomains or 'lipid rafts' that provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes. GEMs are thought to be an important site for signal transduction.
- MICROTUBULE ORGANIZING CENTRE
-
(MTOC). Region in the cell, such as a centrosome or a basal body, from which microtubules grow.
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Acuto, O., Michel, F. CD28-mediated co-stimulation: a quantitative support for TCR signalling. Nat Rev Immunol 3, 939–951 (2003). https://doi.org/10.1038/nri1248
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DOI: https://doi.org/10.1038/nri1248
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