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  • Review Article
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Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling

Nature Reviews Immunology volume 3, pages 544–556 (2003)Cite this article

Key Points

  • The co-stimulatory receptors CD28, inducible co-stimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen 4 (CTLA4) share a common Tyr-Xaa-Xaa-Met motif for the recruitment of phosphatidylinositol 3-kinase (PI3K), which allows for the membrane recruitment and activation of proteins with pleckstrin-homology domains, such as phosphoinositide-dependent kinase 1 (PDK1), protein kinase B (PKB) and glycogen synthase kinase 3 (GSK3). In turn, this implies a role for co-receptors in events such as cellular metabolism, protein translation and apoptosis.

  • Increasing evidence points to CD28 as a signalling unit that can generate intracellular signals independently of the T-cell receptor (TCR).

  • CD28 also has unique properties that are indicated by the presence of a Tyr-Met-Asn-Met motif and several proline residues. The presence of an Asp residue in the plus two position that is absent in ICOS and CTLA4 allows for the binding of growth-factor receptor-bound protein 2 (GRB2), and possibly the binding of GRB2-related adaptor protein (GADS), connecting the co-receptor to VAV and the up-regulation of JUN N-terminal kinase (JNK).

  • Recent studies have implicated PKB, PKC and members of the membrane-associated guanylate kinase (MAGUK) family in the regulation of nuclear factor-κB (NF-κB) and the inhibitor of NF-κB kinase (IKK) complex by CD28.

  • Although ICOS has a Tyr-Xaa-Xaa-Met motif for the binding of PI3K, it lacks other crucial residues that are found in CD28 and CTLA4 and, as a consequence, has a more limited signalling capacity. PI3K–PKB activation might be insufficient to account for ICOS-mediated upregulation of T helper 2 cytokines.

  • Besides binding to PI3K, CTLA4 also has unique proline residues and a Tyr-Val-Lys-Met site that, in a non-phosphorylated state, binds clathrin adaptor complexes, AP1 and AP2. Present models to account for negative signalling include associated phosphatases SHP2 and PP2A.

  • Despite the complexity of co-receptor signalling, the positive versus negative roles of CD28 and CTLA4 on T-cell function is indicated by the ability of the co-receptors to modulate the release of lipid microdomains or rafts to the surface of cells. This will indirectly increase or limit the availability of signalling proteins, such as linker for activation of T cells (LAT), that are required for TCR signalling.

Abstract

Many studies have shown the central importance of the co-receptors CD28, inducible costimulatory molecule (ICOS) and cytotoxic T lymphocyte antigen 4 (CTLA4) in the regulation of many aspects of T-cell function. CD28 and ICOS have both overlapping and distinct functions in the positive regulation of T-cell responses, whereas CTLA4 negatively regulates the response. The signalling pathways that underlie the function of each of the co-receptors indicate their shared and unique properties and provide compelling hints of functions that are as yet uncovered. Here, we outline the shared and distinct signalling events that are associated with each of the co-receptors and provide unifying concepts that are related to signalling functions of these co-receptors.

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Figure 1: Structure of the cytoplasmic domains of human CD28, ICOS and CTLA4.
Figure 2: CD28–PI3K–PDK1–PKB and CD28–VAV pathways.
Figure 3: CD28 and the regulation of NF-κB Pathway.
Figure 4: ICOS signalling pathways.
Figure 5: CTLA4 signalling pathways.
Figure 6: Lipid rafts: integration of positive and negative co-signals.

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Acknowledgements

We wish to apologize to those colleagues whose excellent original work could not be referenced due to space limitations. This has been particularly difficult given the broad scope of the review. We thank J. Williams for her critical reading of the review. Work in the laboratory of C.R. was supported by a Principal Research Fellow award from the Wellcome Trust, UK.

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  1. Department of Immunology, Division of Investigative Science, Molecular Immunology Section, Faculty of Medicine, Imperial College London, Hammersmith Hospital, Du Cane Road, London, W12 ONN, UK

    Christopher E. Rudd & Helga Schneider

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  1. Christopher E. Rudd
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Correspondence to Christopher E. Rudd.

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DATABASES

LocusLink

B7H

BCL10

BIMP1

CARMA1

CD3

CD4

CD7

CD8

CD28

CD80

CD86

CDC42

CTLA4

GADS

GRB2

GSK3

ICOS

IKK

IL-2

IL-4

ITK

JNK

LAT

LCK

LFA1

MEKK1

NFAT

NF-κB

PD1

PDK1

PI3K

PKB

PKC

PP2A

PTEN

RAC1

SLP76

SYK

TIM1

VAV

ZAP70

Glossary

IMMUNOLOGICAL SYNAPSE

A structure that is formed at the cell surface between a T cell and an antigen-presenting cell; also known as the supramolecular activation cluster (SMAC). The T-cell receptor, numerous signal-transduction molecules and adaptors accumulate at this site. Mobilization of the actin cytoskeleton is required for immunological-synapse formation.

D3 LIPIDS

Phosphatidylinositol (4,5)-bisphosphate (PtdIns(4,5)P2) is phosphorylated on the D3 position of the inositol ring to yield phosphatidylinositol (3,4,5)-trisphosphate (PtdInsP3). Conversion of PtdInsP3 to PtdIns(3,4)P2 by SH2-domain-containing inositol phosphatase (SHIP2) can also occur. Different pleckstrin-homology domains bind to PtdInsP3 and/or PtdIns(3,4)P2.

DEATH-INDUCING SIGNALLING COMPLEX

(DISC). A complex that is recruited by the death effector molecule FAS (CD95)-associated death domain protein (FADD), which binds to the cytoplasmic tail of CD95. Leads to the activation of caspase-8 and ultimately induces apoptosis.

LIPID RAFTS

Micro-aggregates of cholesterol- and sphingomyelin-enriched microdomains that are thought to occur in the plasma membrane. Also described as glycolipid-enriched microdomains (GEMs) or detergent-insoluble glycosphingolipid-enriched membrane microdomains (DIGs). They function as platforms that compartmentalize crucial components that are involved in signalling.

MEMBRANE-ASSOCIATED GUANYLATE KINASE FAMILY

MAGUK proteins are defined by a basic core of three domains: a SRC-homology 3 (SH3) domain, a domain with homology to the enzyme guanylate kinase (GUK) and a PDZ domain. They are required for several types of cell-junction formation, contribute to cell shape and seem to hold together elements of individual signalling pathways.

MUCOSA-ASSOCIATED LYMPHOID TISSUE PROTEIN 1

(MALT1). A protein that was first indentified as a casual factor in the development of MALT lymphomas, owing to fusion of the MALT1 gene with the apoptosis inhibitor 2 (API2) gene.

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Rudd, C., Schneider, H. Unifying concepts in CD28, ICOS and CTLA4 co-receptor signalling. Nat Rev Immunol 3, 544–556 (2003). https://doi.org/10.1038/nri1131

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