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The B7–CD28 superfamily

Key Points

  • The B7-1/B7-2–CD28/CTLA-4 co-stimulatory pathway has a crucial role in regulating T-cell activation and tolerance.

  • New B7 and CD28 family members and new pathways have recently been identified that seem to be especially important for regulating the responses of previously activated, rather than antigen-inexperienced, T cells.

  • B7-1 and B7-2 are expressed on professional antigen-presenting cells (APCs), with B7-2 being expressed earlier. B7-2 is more important than B7-1 in initiating T-cell responses. The new B7 homologues are also expressed on cells other than professional APCs, indicating that there might be new mechanisms for regulating T-cell responses in peripheral tissues.

  • In contrast to the constitutive expression of CD28, the CD28 homologue ICOS is induced rapidly on T cells after TCR engagement. ICOS expression is stimulated by both TCR and CD28 signals.

  • The ligand for ICOS (ICOSL) is expressed at low levels on resting B cells, some macrophages and dendritic cells, and can be induced by IFN-γ. ICOSL is also expressed on other cell types, including fibroblasts.

  • Although the signals through CD28 are crucial for the initial co-stimulation of interleukin 2 (IL-2) production, ICOS signals only modestly influence T-cell proliferation and IL-2 production. ICOS signals are most important for regulating cytokine production by recently activated and effector T cells: ICOS can regulate both TH1 and TH2 effector cytokine production, and it has a particularly important role in regulating IL-10 production.

  • ICOS has a crucial role in T-cell–B-cell collaboration and promotes immunoglobulin isotype class switching and germinal centre formation

  • The CD28 family member PD-1 is inducibly expressed on T cells, B cells and myeloid cells, and has an ITIM/ITSM motif in its cytoplasmic domain that recruits SHP-2. PD-1-deficient mice develop late-onset progressive arthritis, lupus-like glomerulonephritis and myocarditis, showing that PD-1 has a role in downregulating immune responses.

  • PD-1 binds to two B7 homologues, PD-L1 (B7-H1) and PD-L2 (B7-DC), but not to other B7 family members. The PD-1 ligands bind to PD-1 but no other CD28 family members. PD-L1 and PD-L2 are expressed in lymphoid and non-lymphoid tissues, and in some tumours.

  • PD-L1 and PD-L2 can inhibit proliferation and cytokine production by previously activated T cells, and can antagonize a B7-2 signal when antigenic stimulation is weak or limiting. Like CTLA-4, PD-1 engagement can lead to cell cycle arrest.

  • Some studies support a role for PD-L1 and PD-L2 in stimulating T-cell responses.

Abstract

The B7-1/B7-2–CD28/CTLA-4 pathway is crucial in regulating T-cell activation and tolerance. New B7 and CD28 molecules have recently been discovered and new pathways have been delineated that seem to be important for regulating the responses of previously activated T cells. Several B7 homologues are expressed on cells other than professional antigen-presenting cells, indicating new mechanisms for regulating T-cell responses in peripheral tissues. Some B7 homologues have unknown receptors, indicating that other immunoregulatory pathways remain to be described. Here, we summarize our current understanding of the new members of the B7 and CD28 families, and discuss their therapeutic potential.

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Figure 1: Structures of the B7-1/B7-2–CD28/CTLA-4 superfamily members.
Figure 2: B7-1 and B7-2 form back-to-back, non-covalent homodimers that interact with covalent homodimers of CD28 or CTLA-4 (Refs 116–118).
Figure 3: ICOS–ICOSL pathway.
Figure 4: PD-1 contains two tyrosines in its cytoplasmic tail, forming ITIM and ITSM motifs.

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Authors

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Correspondence to Arlene H. Sharpe.

Supplementary information

41577_2002_BFnri727_MOESM1_ESM.pdf

Supplementary Table 1 | The CD28 and B7 gene familiesSupplementary Table 2 | Protein sequence similarities between the CD28 and B7 family members* (PDF 55 kb)

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DATABASES

LocusLink

B7-1

B7-2

B7-H3

Bcl-XL

BTN1A1

BTNL2

CD150

CD25

CD28

CD34

CD4

CD40

CD40L

CTLA-4

ERK1

ERK2

fas

GM-CSF

ICOS

ICOSL

IL-10

IL-13

IL-4

IL-5

interferon-γ

interleukin 2

Lyn

myelin oligodendrocyte glycoprotein

PD-1

PD-L1

phospholipase Cγ2

SAP

SHIP

SHP-1

SHP-2

Syk

TNF-α

Vav

Whn

xanthine oxidase

Glossary

TOLERANCE

Unresponsiveness of the adaptive immune system to antigens owing to inactivation or death of antigen-specific lymphocytes induced by exposure to the antigen.

ANERGIC

Rendered unresponsive to antigenic stimulation. The failure of T cell clones to respond to antigen might be a mechanism of maintaining self tolerance.

EFFECTOR

Lymphocyte that performs functions during the effector phases of immune responses, such as producing cytokines (helper T cells), killing cells infected with microorganisms (cytotoxic T cells) or secreting antibodies (differentiated B cells).

IMMUNOGLOBULIN SUPERFAMILY

Share a globular structure called an immunoglobulin (Ig) domain, which was originally described in antibodies. This domain is 110 amino acids long with an internal disulphide bond and two layers of β-pleated sheet. Ig domains are called V-like or C-like, with IgV domains having two extra β-strands and a characteristic DxYxGxC motif at the second Ig cysteine. The B7 and CD28 superfamilies are subsets of the Ig superfamily.

PERIPHERAL T-CELL TOLERANCE

Functional unresponsiveness to self-antigens that are present in peripheral tissues and not usually present in the generative lymphoid organs.

REGULATORY T CELLS

Block the function and/or activation of other T cells. They might exert their effects by secreting cytokines or by cell–cell contact. There are no markers that definitively identify regulatory T cells.

IMMUNORECEPTOR TYROSINE-BASED INHIBITION MOTIF (ITIM)

Six-amino-acid motif (V/IxYxxL/V) found in the cytoplasmic tails of some inhibitory receptors in the immune system. The tyrosine is phosphorylated by Src tyrosine kinases and subsequently binds protein tyrosine phosphatases, which inhibit signal transduction pathways.

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Sharpe, A., Freeman, G. The B7–CD28 superfamily. Nat Rev Immunol 2, 116–126 (2002). https://doi.org/10.1038/nri727

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