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ITAM-mediated tonic signalling through pre-BCR and BCR complexes

Key Points

  • Conventionally, antigen receptors are considered to be inactive until engaged by antigen. However, results from many disparate studies indicate that Igα–Igβ-containing complexes such as the pre-B-cell receptor (pre-BCR) and the B-cell receptor (BCR) can signal independently of ligand engagement, a process that has been termed tonic signalling.

  • Data indicates that the ability to signal independently of ligand engagement is a surprising characteristic of immunoreceptor tyrosine-based activation motif (ITAM)-containing proteins in B cells and their precursors. Plasma-membrane localization is both necessary and sufficient to generate tonic signals from ITAM-containing proteins such as Igα and Igβ.

  • Several mechanisms are proposed to account for the initiation and regulation of tonic signalling. However, it is argued here that most evidence supports a mechanism that involves a sensitive balance between constitutively active protein tyrosine kinases and protein tyrosine phosphatases, which are recruited to tyrosine-phosphorylated immunoreceptor tyrosine-based inhibitory motifs (ITIMs), resulting in transient phosphorylation of Igα and Igβ ITAMs.

  • Tonic signalling might be a unique attribute of ITAM-containing plasma-membrane proteins and might be restricted to haematopoietic cells. All identified transmembrane ITAM-containing proteins are exclusively expressed by haematopoietic cells, coincident with similar restricted expression of ITIM-containing proteins.

  • Certain viruses encode transmembrane proteins that contain ITAMs. In all cases, these are oncogenic viruses with potent transforming potential in non-haematopoietic cells.

  • Virus-encoded ITAM-containing proteins might be previously unidentified oncoproteins for solid-tissue malignancies.

Abstract

Studies carried out over the past few years provide strong support for the idea that Igα–Igβ-containing complexes such as the pre-B-cell receptor and the B-cell receptor can signal independently of ligand engagement, and this has been termed tonic signalling. In this Review, I discuss recent literature that is relevant to the potential mechanisms by which tonic signals are initiated and regulated, and discuss views on how tonic and ligand-dependent (aggregation-mediated) signalling differ. These mechanisms are relevant to the possibility that tonic signals generated through immunoreceptor tyrosine-based activation motif (ITAM)-containing proteins that are expressed by oncogenic viruses induce transformation in non-haematopoietic cells.

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Figure 1: Structural and functional characterization of the pre-BCR and BCR.
Figure 2: Aggregation-induced BCR-proximal signalling.
Figure 3: Equilibrium model for maintaining the resting state of non-aggregated Igα–Igβ complexes.
Figure 4: Proposed model to integrate tonic and ligand-induced aggregation-dependent signalling processes.

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Acknowledgements

I wish to thank S. Grande for her help in preparing this Review. I also acknowledge the help of L. King and J. Stadanlick for organizational and content editing.

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Glossary

Complementarity-determining region

(CDR). The most variable parts of immunoglobulins and T-cell receptors, which form loops that make contact with specific ligands. There are three such regions (CDR1, CDR2 and CDR3) in each variable domain.

Immunoreceptor tyrosine-based activation motif

(ITAM). B-cell, T-cell and natural-killer-cell receptors are non-covalently associated with transmembrane proteins that contain one or more ITAMs. The amino-acid sequence of an ITAM is (D/E)XXYXX(L/I)X6–8 YXX(L/I), where X denotes any amino acid. This is tyrosine phosphorylated after engagement of the ligand-binding subunits, which triggers a cascade of intracellular events that results in cellular activation.

SRC-family protein tyrosine kinases

These kinases are characterized by SRC homology 2 (SH2) and SH3 protein-interaction domains and their amino-terminal unique region contains sites for fatty-acid modification. Modification by myristoylation and in many (but not all) cases palmitoylation facilitates membrane localization of these kinases.

SRC homology 2 domain

(SH2 domain). A protein-interaction domain that is commonly found in signal-transduction molecules. It specifically interacts with phosphotyrosine-containing peptides.

Immunoreceptor tyrosine-based inhibitory motif

(ITIM). YXXL-based motifs (where X denotes any amino acid) that are similar in sequence to immunoreceptor tyrosine-based activation motifs (ITAMs). They function by recruitment of SRC homology 2 (SH2)-domain-containing phosphatases. Expression of ITIM-containing proteins is largely confined to haematopoietic cells and is therefore thought to be mainly involved in the regulation of ITAM-based signalling, although exceptions to this rule have been proposed.

Lipid raft

Glycosphingolipid- and cholesterol-enriched plasma-membrane microdomains that have been proposed to function as signalling platforms for many receptors. They are often defined by their composition, as well as their physical characteristics, which include resistance to solubilization in mild detergents at 4°C.

Pre-B cells

Cells at a stage of B-cell development in the bone marrow that are characterized by complete immunoglobulin-heavy-chain (IgH) rearrangement in the absence of immunoglobulin-light-chain rearrangement. They express the pre-B-cell receptor, which comprises a surrogate light chain and an IgH. Cells are defined as CD19+cytoplasmic IgM+ or, sometimes, as B220+CD43 cell-surface IgM (by the Hardy classification scheme).

Pro-B cells

Cells at the earliest stage of B-cell development in the bone marrow. They are characterized by incomplete immunoglobulin-heavy-chain rearrangements and are defined as CD19+cytoplasmic IgM or, sometimes, as B220+CD43+ (by the Hardy classification scheme).

μMT mice

Genetically engineered mice that lack one of the exons necessary for transmembrane localization of the immunoglobulin heavy chain. Therefore, although B cells from these mice are able to assemble the pre-B-cell receptor (pre-BCR), they are unable to localize it to the plasma membrane. Because they lack the ability to generate pre-BCR signals, the maturation of B cells in these mice is arrested at the pro-B-cellpre–B-cell checkpoint.

Immature B cell

The first stage of B-cell development at which the mature form of the B-cell receptor (BCR) is expressed. In the bone marrow, these are termed immature B cells, and in the periphery, they are called transitional immature B cells. These B cells are especially directed towards fates that are linked with negative selection and tolerance when they encounter antigen.

Cre–loxP

The Cre (cyclization recombinase) protein from bacteriophage P1 excises DNA that is flanked by recombination sequences called loxP sites. These sequences can be introduced at either end of a gene by homologous recombination. Animals carrying loxP-flanked genes can be made transgenic for Cre, which can be placed under a tissue-specific or inducible promoter. In the cells that express Cre, the loxP sites are recognized, and the DNA between them is excised, leading to tissue-specific or inducible deletion of the gene of interest.

Endoplasmic-reticulum stress

An evolutionarily conserved response to the accumulation of misfolded proteins in the endoplasmic reticulum. This stress can trigger adaptive programmes that limit continued protein synthesis and facilitate elimination of misfolded proteins. Alternatively, apoptotic programmes are linked to stress responses where the levels of misfolded proteins cannot be decreased.

Follicular CD23+ B cell

A recirculating mature B-cell subset that populates the follicles of the spleen and lymph nodes.

Reactive oxygen species

(ROS). Oxygen radicals that are produced by the mitochondrial respiratory chain and, as discussed here, by receptor signalling at the plamsa membrane. In excess, they can cause intracellular and mitochondrial damage, which promotes cell death. However, studies also indicate their involvement in stabilization of receptor-induced activation signals through their ability to inhibit protein tyrosine phosphatases.

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Monroe, J. ITAM-mediated tonic signalling through pre-BCR and BCR complexes. Nat Rev Immunol 6, 283–294 (2006). https://doi.org/10.1038/nri1808

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