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  • Review Article
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T-cell regulation by CD28 and CTLA-4

Key Points

  • The numbers of T-cell receptors (TCRs) engaged, as well as the time of interaction with the major histocompatibility complex (MHC)–peptide complexes, determine whether T-cell activation occurs.

  • Absence of Jun N-terminal kinase (JNK) activity results in augmented interleukin-2 (IL-2) production and proliferation by normal T cells, and increased production of TH2-type cytokines following priming.

  • CD28 crosslinking reduces the number of TCRs that need to be engaged, as well as the time required for T cells to interact with antigen, and enhances the magnitude of the T-cell response.

  • On TCR stimulation, CD28 signalling quantitatively augments TCR-mediated signals, as well as activating independent pathways. The Y170 in the cytoplasmic tail of CD28 seems important for BCL-XL upregulation and might contribute to CD28-mediated cytokine production and proliferation. This latter function might also be controlled by the C-terminal proline-rich region of CD28.

  • Cytotoxic T-lymphocyte antigen 4 (CTLA-4) ligation raises the threshold needed for T-cell activation and arrests T-cell-cycle progression.

  • The role of CTLA-4 in tolerance induction and its capacity to impart inhibitory function to regulatory CD25+/CD4+ T cells is controversial.

  • CTLA-4 functions both by scavenging CD80/86 ligands away from CD28 and by direct negative signalling to T cells. Phosphorylation of the two tyrosine residues in the cytoplasmic tail of CTLA-4 is not necessary for CTLA-4 to deliver its inhibitory signal.

Abstract

Activation of T lymphocytes is thought to require at least two signals, one delivered by the T-cell receptor complex after antigen recognition, and one provided on engagement of co-stimulatory receptors, such as CD28. Recent studies are providing clues as to the specific signalling roles of co-stimulatory receptors. Furthermore, superimposition of inhibitory signals, such as those delivered by cytotoxic T-lymphocyte antigen 4 (CTLA-4), leads to a complex network of positive and negative co-stimulatory signals, the integration of which modulates immune responses.

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Figure 1: T-cell fate under different conditions of TCR engagement.
Figure 2: Model for CD28 signalling.
Figure 3: Schematic representation of the lattice network created by CTLA-4 binding to CD80/86 ligands.
Figure 4: Model for CTLA-4 signalling.

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Correspondence to Maria-Luisa Alegre.

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DATABASES

LocusLink

Akt

AP50

BCL-XL

CD3ζ

CD28

CD80

CD86

CD152

Fyn

Grb2

IFN-γ

IL-2

IL-4

IL-5

IL-10

IL-13

ITK

Jak-2

Jnk1

Jnk2

Lck

Lyn

PTEN

Rlk

SHC

SHP-2

ZAP70

FURTHER INFORMATION

Maria-Luisa Alegre's lab

Encyclopedia of sciences

T lymphocye responses: development

Glossary

AGONIST PEPTIDES

Peptides that mimic cognate antigen and result in T-cell activation and proliferation.

ANTAGONIST PEPTIDES

Peptides that prevent T-cell activation by cognate antigen either by competition for TCR sites or by active delivery of negative signals.

ANERGY

State of T cells stimulated by their T-cell receptors in the absence of CD28 ligation. On restimulation, these T cells are unable to make IL-2 or to proliferate even in the presence of co-stimulatory signals.

CYCLOSPORIN A

Immunosuppressive drug that inhibits calcineurin, a Ca2+-dependent serine/threonine phosphatase neccessary for the nuclear translocation of the transcription factor NF-AT.

LIPID RAFTS

Cholesterol-rich regions that provide ordered structure to the lipid bilayer and have the ability to include or exclude specific signalling molecules and complexes.

GRAFT-VERSUS-HOST DISEASE

The immune reaction against a graft recipient mounted by immune-competent cells of a graft.

DOMINANT-NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

TOLERANCE

T cells that, on TCR restimulation, cannot produce IL-2 and proliferate are termed tolerant. An initial such description was that of anergic T cells, which define T cells obtained after engagement of the TCR in the absence of CD28 ligation in vitro. Several manipulations in vivo have since been shown to generate tolerant T cells, including systemic injection of antigen or superantigen in the absence of adjuvant, and intranasal or oral administration of antigen.

YEAST TWO-HYBRID SCREENING

System used to determine the existence of direct interactions between proteins. It involves the use of plasmids that encode two hybrid proteins; one of them is fused to the GAL4 DNA-binding domain and the other one is fused to the GAL4 activation domain. The two proteins are expressed together in yeast and, if they interact, then the resulting complex will drive the expression of a reporter gene, commonly β-galactosidase.

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Alegre, ML., Frauwirth, K. & Thompson, C. T-cell regulation by CD28 and CTLA-4. Nat Rev Immunol 1, 220–228 (2001). https://doi.org/10.1038/35105024

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