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Balancing co-stimulation and inhibition with BTLA and HVEM

Key Points

  • Herpesvirus-entry mediator (HVEM) is a co-stimulatory member of the tumour-necrosis factor (TNF) family of receptors that are expressed by T cells. It interacts with TNF family members LIGHT and lymphotoxin-α (LTα). It has also recently been shown to have an unusual interaction with B- and T-lymphocyte attenuator (BTLA), an inhibitory molecule expressed by T cells, such as cytotoxic T-lymphocyte antigen 4 (CTLA4) and programmed cell death 1 (PD1).

  • Trimeric LIGHT or LTα proteins are likely to induce trimerization of HVEM receptors. By contrast, structural studies have shown that BTLA interacts with a different surface of the HVEM molecule compared with LIGHT, inducing a dimer, and leading to the possibility of a ternary complex containing HVEM, LIGHT and BTLA.

  • HVEM, LIGHT, and BTLA are all widely expressed on T cells and antigen presenting cells. The expression of each of these receptors is dynamically regulated: HVEM expression generally decreases with activation, whereas LIGHT and BTLA expression generally increases with activation.

  • BTLA, like CTLA4 and PD1, recruits Src homology 2 (SH2)-domain-containing protein tyrosine phosphatases (SHPs) to its cytoplasmic domain following HVEM ligation. These phosphatases have been shown to block T-cell-receptor signal transduction after CTLA4 or PD1 ligation.

  • HVEM co-stimulates T-cell activation following ligation with LIGHT. HVEM has co-stimulatory effects on many other cells including B cells, dendritic cells, natural killer cells, monocytes and neutrophils that result in increases in proliferation and activation.

  • Mice deficient in LIGHT show clear defects in T-cell activation. Mice deficient in HVEM and BTLA, however, both show defects in T-cell inhibition, further indicating the linkage of these two proteins in vivo.

Abstract

The interaction between B- and T-lymphocyte attenuator (BTLA), an inhibitory receptor whose extracellular domain belongs to the immunoglobulin superfamily, and herpesvirus-entry mediator (HVEM), a co-stimulatory tumour-necrosis factor receptor, is unique in that it is the only receptor–ligand interaction that directly bridges these two families of receptors. This interaction has raised many questions about how receptors from two different families could interact and what downstream signalling events might occur as a result of receptor ligation. As we discuss, recent studies show that engagement of HVEM with its endogenous ligand (LIGHT) from the tumour-necrosis factor family induces a powerful immune response, whereas HVEM interactions with BTLA negatively regulate T-cell responses.

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Figure 1: Molecular interactions between TNFRs, TNFs and immunoglobulin-domain-containing receptors.
Figure 2: Molecular modelling of herpesvirus-entry mediator and its ligands.
Figure 3: Expression of HVEM, BTLA and LIGHT is dynamically regulated on T cells and antigen-presenting cells.
Figure 4: CTLA4, PD1 and BTLA regulate T-cell activation.
Figure 5: HVEM co-stimulates many cell types within the lymphoid compartment.

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Acknowledgements

The authors would like to thank M. Hurchla, P. Wilker and A.V. Miletic Šedý for critical reading of the manuscript.

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Glossary

Co-stimulatory signals

Optimal signalling through the T-cell or B-cell receptor complex requires accessory cell-surface molecules, such as CD28, inducible T-cell co-stimulator (ICOS) and members of the tumour-necrosis factor receptor family. These co-stimulatory signals synergize with primary signals that promote the proliferation and effector function of these lymphocytes and of other cell types.

Immunoglobulin superfamily

A family of proteins that contain immunoglobulin domains. Immunoglobulin domains themselves are made up of 7–9 β-strands and often mediate protein–protein interactions.

T-helper (TH) cells

TH cells secrete distinct patterns of cytokines after activation, which occurs through ligation of their T-cell receptors with their cognate ligands (peptide–MHC complexes), together with recognition of the appropriate co-stimulatory molecules. Undifferentiated TH0 cells differentiate (or polarize) into TH1 or TH2 cells, depending on the cytokines and co-stimulatory molecules presented to them by antigen-presenting cells.

Tetramers

A staining reagent consisting of the biotinylated recombinant extracellular domain of a cell-surface receptor bound onto a fluorochrome-coupled streptavidin support. The resulting tetramer can be used to identify cells expressing ligands for the cell-surface receptor. Tetramers are commonly made from MHC-class-I complexes to identify CD8+ T-cell populations.

Retroviral cDNA library

A eukaryotic RNA-transcript-expression library in which mouse cDNA is introduced into a retroviral construct and packaged into a retrovirus capable of a single infection. This retrovirus is then stably introduced into cell lines in order to clonally express all cDNAs, which are then screened for clones of interest.

Surface-plasmon resonance

A technique used to measure molecular interactions by observing how much of an input molecule (for example, a protein) is bound to a chip adsorbed with another molecule. The amount of bound input is directly proportional to the change in the light reflected off the adsorbed chip, which is specifically measured. This technique can be used to calculate single-molecule affinities as well as binding on and off rates.

Size exclusion chromatography

A technique used to separate solution-phase molecular complexes on the basis of their hydrodynamic radius, which is related to their overall molecular weight. This technique is also useful for isolating non-covalently bound complexes.

Germinal centre

Structures located in peripheral lymphoid tissues such as the spleen. They are sites of B-cell proliferation and selection of clones that produce antigen-specific antibodies of higher affinity.

Protein kinase B

A serine/threonine kinase that is activated following recruitment to the lipid membrane by phosphatidylinositol 3-kinase (PI3K) and phosphorylation by 3-phosphoinositide-dependent protein kinase (PDK), and can regulate cell division and cell survival through actions on cell-cycle inhibitors and both pro- and anti-apoptotic members of the B-cell lymphoma 2 (BCL2) family.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). This motif is present in the cytoplasmic domain of several inhibitory receptors. After ligand binding, ITIMs are tyrosine phosphorylated and recruit inhibitory phosphatases.

Nuclear factor-κB

A family of transcription factors that are important for pro-inflammatory and anti-apoptotic responses. They are activated by the phosphorylation and subsequent ubiquitin-dependent proteolytic degradation of inhibitory proteins following mitogenic signals.

Activator protein 1

A transcription-factor complex composed of a heterodimer of JUN and FOS subunits that is necessary for the induction of interleukin-2 transcription in T cells. JUN and FOS subunits are members of a family of leucine-zipper-containing proteins that are induced by mitogenic stimuli.

Mixed lymphocyte reaction

A tissue-culture technique for testing T-cell reactivity. The proliferation of one population of T cells, induced by exposure to inactivated MHC-mismatched stimulator cells, is determined by measuring the incorporation of 3H-thymidine into the DNA of dividing cells.

IgA nephropathy

A form of glomerulonephritis in which defective IgA transport to the gut lumen leads to increased serum IgA levels and renal deposition.

Concanavalin A

A plant lectin that functions as a T-cell mitogen.

Experimental autoimmune encephalomyelitis

An experimental model of multiple sclerosis that is induced by immunization of susceptible animals with myelin-derived antigens such as myelin basic protein, proteolipid protein or myelin oligodendrocyte glycoprotein.

Polymorphisms

Single-nucleotide differences in the sequence of genes that represent allelic variants. These differences might lead to altered structure and/or altered expression of gene products, ultimately leading to pathology.

Systemic lupus erythematosus

(SLE). An autoimmune disease in which autoantibodies that are specific for DNA, RNA or proteins associated with nucleic acids form immune complexes that damage small blood vessels, especially in the kidneys. Patients with SLE generally have abnormal B- and T-cell function.

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Murphy, K., Nelson, C. & Šedý, J. Balancing co-stimulation and inhibition with BTLA and HVEM. Nat Rev Immunol 6, 671–681 (2006). https://doi.org/10.1038/nri1917

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