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  • Review Article
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Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity

Nature Reviews Immunology volume 4, pages 336–347 (2004)Cite this article

Key Points

  • Co-signalling molecules, including co-stimulators and co-inhibitors, form a co-signalling network to positively and negatively regulate immune responses.

  • Co-signalling molecules can potentially function as either receptors or ligands, and the functional outcome depends on the cells that express them.

  • Several pathways of co-inhibitors in the B7–CD28 family have been identified — CD80/CD86–CTLA4 (cytotoxic T lymphocyte antigen 4), B7-H1/B7-DC–PD1 (programmed cell death 1), B7-H4 and BTLA (B and T lymphocyte attenuator).

  • Co-inhibitory functions are normal mechanisms that maintain homeostasis in the host.

  • Cancer and autoimmune diseases have exploited co-inhibitors in their pathogenic processes.

  • Manipulation of co-inhibitory pathways provides a promising approach for the development of new therapeutics for human diseases, including cancer, autoimmune diseases, viral infection and transplantation rejection.

Abstract

Co-signalling molecules are cell-surface glycoproteins that can direct, modulate and fine-tune T-cell receptor (TCR) signals. On the basis of their functional outcome, co-signalling molecules can be divided into co-stimulators and co-inhibitors, which promote or suppress T-cell activation, respectively. By expression at the appropriate time and location, co-signalling molecules positively and negatively control the priming, growth, differentiation and functional maturation of a T-cell response. We are now beginning to understand the power of co-inhibitors in the context of lymphocyte homeostasis and the pathogenesis of human diseases. In this article, I focus on several newly described co-inhibitory pathways in the B7–CD28 family.

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Figure 1: The B7–CD28-family molecules with co-inhibitory functions.
Figure 2: Models of co-signalling in T-cell activation.
Figure 3: The co-signal network model.
Figure 4: The B7–CD28 family co-inhibitor axis.

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Authors and Affiliations

  1. Department of Dermatology, Department of Oncology and Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, 21287, Maryland, USA

    Lieping Chen

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  1. Lieping Chen
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DATABASES

LocusLink

B7-DC

B7-H1

B7-H3

B7-H4

BTLA

CD28

CD80

CD86

CD154

CTLA4

GM-CSF

ICOS

IDO

IFN-γ

IL-4

IL-10

PD1

SHP1

SHP2

TNF

TRAIL

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 supra-molecular activation cluster (SMAC). Important molecules involved in T-cell activation — including the T-cell receptor, numerous signal transduction molecules and molecular adaptors — accumulate at this site. Mobilization of the actin cytoskeleton of the cell is required for immunological-synapse formation.

CO-STIMULATORS

Molecules that stimulate naive or activated T cells in the presence of a T-cell receptor signal by binding to a co-stimulatory receptor, leading to the induction of T-cell growth, differentiation and functional maturation.

CO-INHIBITORS

Molecules that inhibit T-cell responses by binding co-inhibitory receptors only in the presence of a T-cell receptor signal. This can inhibit T-cell growth and functional maturation, and induce tolerance/anergy of T cells.

REVERSE SIGNALLING

In some cases, a ligand can receive a signal from its counter-receptor, so that the ligand could function as a typical receptor.

GRAFT-VERSUS-HOST DISEASE

(GVHD). An immune response mounted against the recipient of an allograft by immunocompetent donor T cells derived from the graft. Typically, it is seen in the context of allogeneic bone-marrow transplantation.

IMMUNORECEPTOR TYROSINE-BASED INHIBITORY MOTIF

(ITIM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several inhibitory receptors. The prototype six-amino-acid ITIM sequence is (Ile/Val/Leu/Ser)-Xaa-Tyr-Xaa-Xaa-(Leu/Val). Ligand-induced clustering of these inhibitory receptors results in tyrosine phosphorylation, often by SRC-family tyrosine kinases, which provides a docking site for the recruitment of cytoplasmic phosphatases that have an SH2 domain.

IMMUNORECEPTOR TYROSINE-BASED SWITCH MOTIF

(ITSM). A structural motif containing tyrosine residues that is found in the cytoplasmic tails of several CD2-family molecules, such as CD84, CD229, CD244, NTB-A and CS1. The prototype six-amino- acid ITSM sequence is Thr-Xaa-Tyr-Xaa-Xaa-(Val/Ile). The receptors with ITSMs are bound and regulated by small SH2-domain-containing adaptor proteins such as SH2D1A and EAT2, leading to association with other SH2-domain-containing molecules, which functions as a signalling 'switch'.

NEGATIVE SELECTION

The deletion of self-reactive thymocytes in the thymus. Thymocytes expressing T-cell receptors that strongly recognize self-peptide bound to self-MHC undergo apoptosis in response to the signalling generated by high-affinity binding.

EXPRESSED-SEQUENCE TAG DATABASE

By searching the expressed-sequence tag database, several overlapping sequence fragments can be assembled into a full-length gene.

2C-TCR-TRANSGENIC MICE

A transgenic mouse strain in which most CD8+ T cells express a transgenic T-cell receptor (TCR) that recognizes an allogeneic antigen.

TRANSPLANT ATHEROSCLEROSIS

Thickened and hardened lesions of arteries in transplants, usually caused by chronic rejection responses.

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Chen, L. Co-inhibitory molecules of the B7–CD28 family in the control of T-cell immunity. Nat Rev Immunol 4, 336–347 (2004). https://doi.org/10.1038/nri1349

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