B Lymphocytes: Receptors

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B Lymphocytes: Receptors

Anthony L DeFranco, University of California, San Francisco, California, USA

Published online: November 2015

DOI: 10.1002/9780470015902.a0000914.pub3

Full Article on Wiley Online Library

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Abstract

B lymphocytes can synthesise Ig heavy chains that are either secreted or membrane‐bound, the latter having a transmembrane domain and a short cytoplasmic domain. Membrane‐bound Ig heavy chains and Ig light chains assemble in the ER with each other and with a heterodimer of Igα and Igβ, which mediate signalling and internalisation functions. The complex of these four polypeptides is called the B cell antigen receptor (BCR). BCR signalling occurs via three types of tyrosine kinases. Src‐family kinases phosphorylate the two tyrosine‐containing motif in the cytoplasmic domains of Igα and Igβ (the ITAMs), which recruits a second type of tyrosine kinase Syk. Syk is responsible for most downstream signalling, although calcium and diacylglycerol also require a third tyrosine kinase Btk. BCR signalling pathways are central to virtually all aspects of B cell biology, as they are required for B cell development, tolerance induction, survival and activation.

Key Concepts

Naïve B cells express their immunoglobulin as a cell surface receptor for antigen, called the BCR (B cell receptor for antigen).
In developing precursors of B cells, the successful generation of an immunoglobulin heavy chain is sensed by the incorporation of that heavy chain into pre‐BCR molecules, which exhibit constitutive signalling.
Signalling by the BCR controls development, survival and activation of B cells in a manner that is dependent on the developmental stage or activation state of the B cell. This signalling is important both for tolerisation of self‐reactive B cells and for activation of B cells recognising foreign antigen.
Co‐receptors that recognise complement components, sialic acid residues, or IgG bound to antigens strongly enhance or inhibit signalling by the BCR to aid in self‐non‐self‐discrimination.
The BCR is also an endocytic receptor that delivers antigen to internal compartments where protein antigens are processed into peptides and loaded onto MHC class II molecules to facilitate interactions with T cells, which are essential for production of high‐affinity antibodies.
Defects in generation of BCRs or signalling components of the BCR result in B cell immunodeficiencies, the most common of which is due to loss‐of‐function mutations of the intracellular protein tyrosine kinase Btk, referred to as X‐linked agammaglobulinemia.
B cell malignancies often have activated BCR signalling as a driver of their proliferation and/or survival, and selective Btk inhibitors are now approved therapeutics for some types of B cell malignancies.

Keywords: antibody; membrane immunoglobulin; BCR; pre‐BCR; protein tyrosine kinase; Syk; Btk; ITAM; phosphoinositide signalling

	Figure 1. Structure of the BCR and the pre‐BCR. The BCR and pre‐BCR are analogous structures with the main difference being the presence in the BCR of a κ or λ light chain and the presence in the pre‐BCR of ‘surrogate light chain’, composed of VpreB and λ5. The non‐Ig domain parts of the surrogate light chain (represented by curving lines) provide a function that is required for B cell development, as discussed in the text. Box in the cytoplasmic domain of Igα and Igβ represents the ITAM sequence.
	Figure 2. Schematic overview of the antibody response. See the text for details.
	Figure 3. Antigen binding to the BCR triggers the following series of events: (1) phosphorylation of BCR ITAM tyrosines by the Src‐family tyrosine kinases (Lyn, Fyn and Blk); (2) binding of Syk to doubly phosphorylated ITAMs via its two SH2 domains (represented by oval indentations); (3) activation of Syk by a combination of binding via its SH2 domains and activating phosphorylations performed by neighbouring protein tyrosine kinases (Src‐family tyrosine kinases or Syk bound to a co‐clustered BCR) and (4) phosphorylation of tyrosines of signalling target molecules primarily by Syk but to some extent by Src family kinases. ‘P’ represents phosphorylated tyrosine residue.
	Figure 4. BCR engagement induces the formation of signalling complexes. Two major signalling complexes are formed in response to BCR engagement. Left: SLP65 (also called BLNK) is pre‐associated with Cbl‐interacting protein of 85 kDa (CIN85) via interaction of proline‐rich motifs of SLP65 with the three SH3 domains of CIN85. Upon engagement of the BCR, CIN85 is recruited to the BCR, but the exact mechanism of this recruitment is not well defined. Upon recruitment, Syk phosphorylates multiple tyrosines in the N‐terminal region of SLP65, which in turn recruit PLCγ2, Btk and Vav. Btk becomes activated by phosphorylation and participates in the activation of PLCγ2 by phosphorylating it. Not shown, recruitment of Btk and PLCγ2 to SLP65 is aided by pleckstrin homology (PH) domains of these proteins, which have specificity for PIP₃. In addition, the C‐terminal SH2‐domain of SLP65 can bind to a non‐ITAM‐phosphorylated tyrosine of Igα (Y204), but this interaction is not required for SLP65 function, at least under conditions of vigorous signalling. Right: PI 3‐kinase is activated following BCR engagement by two main mechanisms. CD19 has two tyrosines in its cytoplasmic domain that serve as binding sites for the SH2 domain of the regulatory subunit of PI 3‐kinase (p85, shown in blue), which is pre‐bound to the catalytic p110 subunit (shown in orange). This mechanism is especially important if the antigen has complement components deposited on it, as CD19 is in a complex with CR2 (CR2, also called CD21) (Figure a), but it is also important if the antigen is attached to a cell surface. In addition, PI 3‐kinase is recruited to the BCR and activated via a complex between Nck and BCAP, which forms due to the SH3 domains of Nck1 or Nck2 binding to proline‐rich regions of BCAP. The SH2 domain of Nck binds to tyrosine‐phosphorylated Y204 of Igα, which recruits BCAP, leading to its phosphorylation and recruitment to the membrane of PI 3‐kinase. Nck and Vav also both participate in regulation of actin remodelling, which is also an important element of BCR signalling. SLP65 and Nck compete for binding to tyrosine‐phosphorylated Y204 of Igα; current evidence indicates that the Nck interaction is the more important one. Not shown is that BCR engagement also leads to assembly of the CARMA‐1, Bcl‐10, MALT1 complex that activates NF‐κB. SH3 domains in Nck and CIN85 are indicated. SH2 domains of significance are indicated by oval indentations. Other important protein domains such as PH domains are not shown.
	Figure 5. Signalling pathways involving phosphoinositol‐containing phospholipids. Shown in red are the key second messengers generated by PLCγ2 and PI 3‐kinase, the two upstream enzymes acting on PIP₂. In blue are the key enzymes that are activated by these second messengers, which includes PLCγ2, representing a connection between the two major pathways. Note that protein kinase C (PKC) comes in multiple isoforms and the isoform involved in NF‐κB activation is PKCβ. PKCδ has also been shown to be important for regulating B cell function, but how it is activated and its key targets are not well defined. Inhibitory enzymes are in orange. DG, diacylglycerol and IP₃+, inositol 1,4,5‐trisphosphate. See the text for details.
	Figure 6. (a): The complement receptor 2 (CR2, also called CD21) complex on B cells is a positive co‐receptor that can greatly enhance B cell activation. The presence of complement fragments (breakdown fragments of C3b, including C3d) attached to the antigen recruit the CR2 complex of B cells, which includes CD19 and the tetraspanin CD81, to the membrane near the BCR. BCR‐associated protein tyrosine kinases such as Syk then phosphorylate the cytoplasmic tail of CD19, which creates binding sites for the p85 regulatory subunit of PI 3‐kinase. PI 3‐kinase is recruited to the membrane where it has access to its substrate PIP₂ (see Figure ). This mechanism is thought to represent a means of self‐non‐self‐discrimination, as the alternative pathway of complement or low‐affinity IgM can promote C3b deposition on foreign particles or debris, whereas host cells have complement inhibitory proteins on their surface that rapidly destroy any complement components that may be deposited on them. (b): Inhibitory co‐receptors of B cells can inhibit activation of B cells if there are already sufficient levels of circulating IgG recognising the antigen (left) or if the antigen contains terminal sialic acid residues in linkages characteristic of self‐oligosaccharides on glycoproteins or glycolipids (right). FcγRIIb and the Siglec family members CD22 and Siglec G (not shown) are inhibitory receptors with one or more tyrosine‐containing ITIM motifs in their cytoplasmic domains. Once phosphorylated, these motifs recruit either the SH2‐containing inositol phosphatase (SHIP), which removes a phosphate from PIP₃ and thereby counters PI 3‐kinase signalling (see Figure ), or the SH2‐containing protein tyrosine phosphatase SHP‐1 (also called PTPN6), which counters signalling by Syk and Src‐family tyrosine kinases at proximal steps. Among the Src‐family tyrosine kinases, only Lyn can phosphorylate ITIMs, whereas Lyn, Fyn and Blk are all able to phosphorylate ITAMs and contribute positively to BCR signalling. While this figure emphasises the role of CD22 in inhibiting BCR signalling when the antigen has sialic acid bound to it, CD22 also attenuates BCR signalling in a manner that is controlled by lateral interactions with sialic acid‐containing glycoproteins on the B cell surface (not shown).

Article Title:	B Lymphocytes: Receptors
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