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  • Review Article
  • Published:

The follicular versus marginal zone B lymphocyte cell fate decision

Key Points

  • The follicular versus marginal zone B lymphocyte cell fate decision is an important event during peripheral B cell differentiation.

  • Cells are selected to differentiate into these two subsets based in part on the strength of B cell receptor (BCR) signalling in individual cells.

  • Stronger BCR signals favour the development of follicular type I B cells, and weaker signals favour the development of marginal zone B cells.

  • Tonic BCR signalling and B cell-activating factor (BAFF) are sufficient for the induction of follicular type II B cells.

  • Canonical nuclear factor-κB (NF-κB) signalling downstream of the BAFF receptor is essential for marginal zone B cell development

  • BCR-mediated activation of Bruton's tyrosine kinase and B cell adaptor for phosphoinositide 3-kinase-dependent induction of REL are required for follicular type I B cell development.

  • Sialic acid acetyl esterase is part of an inhibitory signalling pathway that sets thresholds for BCR signalling and in the absence of which marginal zone B cell development is compromised.

  • Signalling through Notch2 on B cells is also crucial for marginal zone B cell development.

  • Splenic red pulp and marginal zone venules are the main source of delta-like 1 (DL1), an important ligand for Notch2 during peripheral B cell maturation

  • Mindbomb1 is an E3 ligase that is crucial for the endocytosis of DL1 and marginal zone B cell development.

  • Notch2 might regulate the follicular versus marginal zone B cell fate decision by regulating the turnover of E2A proteins.

  • Integrins have a crucial role in marginal zone B cell retention and possibly survival.

Abstract

Bone marrow-derived B cells make an important cell fate choice to develop into either follicular B cells or marginal zone B cells in the spleen, which depends on signalling through the B cell receptor, Notch2, the receptor for B cell-activating factor and the canonical nuclear factor-κB pathway, as well as signals involved in the migration and anatomical retention of marginal zone B cells. Recent information discussed in this Review reconciles some of the controversies regarding the role of the B cell receptor in this cell fate decision and a clearer picture has also emerged regarding the anatomical location of ligands for Notch2 in the spleen. This cell fate decision could provide mechanistic insights that are relevant to other commitment events in lymphocytes.

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Figure 1: A sequential model for marginal zone B cell development.
Figure 2: Signals required for commitment to a B cell fate.
Figure 3: A schematic view of the anatomy of the spleen.

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Acknowledgements

This work was supported by grants AI064930, AO076505, and AR058481 from the US National Institutes of Health.

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Glossary

B cell follicle

An aggregate of B cells in lymphoid tissues. It contains naive B cells, as well as activated, proliferating and maturing B cells in germinal centres. B cell follicles are contiguous with T cell zones.

Sinusoid

A blood-filled space that lacks the anatomy of a capillary. Sinusoids generally contain slow-flowing blood, which facilitates cellular interactions. Such vessels are found in the bone marrow, spleen and liver.

Invariant natural killer T (iNKT) cell

A T cell that expresses a particular variable gene segment — Vα14 in mice and Vα24 in humans — precisely rearranged to a particular J (joining) gene segment to yield a T cell receptor α-chain with an invariant sequence. Typically, these cells co-express cell surface markers that are encoded by the natural killer locus, and they are activated by recognition of CD1d, particularly when α-galactosylceramide is bound in the groove of CD1d.

Receptor editing

A process that involves secondary rearrangements of B cell receptor genes and the replacement of existing immunoglobulin molecules (mostly of the light chains), which results in the generation of a new antigen receptor with altered specificity.

Anergy

A state of non-responsiveness to antigen. Anergic T or B cells cannot respond to their cognate antigens under optimal conditions of stimulation.

Canonical nuclear factor-κB (NF-κB) pathway

A typical pathway of NF-κB activation that involves phosphorylation and degradation of the prototypical NF-κB inhibitor IκBα, and requires activation of the IKKβ component of the IκB kinase (IKK) complex.

Positive selection

The survival of developing lymphocytes with 'desirable' antigen receptors is favoured by the processes of positive selection, which include cessation of V(D)J recombination and developmental progression.

X-linked immunodeficient (Xid) mice

Mice with a naturally occurring point mutation in Btk that have defects in follicular type I B cells and in B-1 B cells. They are phenotypically identical to Btk-deficient mice.

Aiolos-deficient mice

Mice engineered to be deficient in Aiolos, an Ikaros family heterochromatin protein that functions as a negative regulator of the B cell receptor.

Immunoreceptor tyrosine-based activation motif

A short peptide motif containing tyrosine residues that is found in the cytoplasmic tails of several signalling molecules and in adaptors such as DNAX activation protein12. The consensus sequence is (Asp or Glu)-X-X-Tyr-X-X-(Leu or Ile)-X6–8-Tyr-X-X-(Leu/Ile), with X denoting any amino acid. It is tyrosine phosphorylated after engagement of the ligand-binding subunits, which triggers a cascade of intracellular events that usually results in cellular activation.

Non-canonical NF-κB pathway

A pathway of NF-κB activation that does not involve IκBα degradation but relies on the processing of an NF-κB precursor protein, p100, to p52, leading to nuclear translocation of p52–RELB NF-κB heterodimers.

BCL-10–MALT1–CARMA1 complex

A trimeric protein complex that can be activated by protein kinase C and helps, in a lysine-63 ubiquitylation-dependent manner, to link the IKK complex to upstream activating kinases during antigen-receptor-dependent canonical NF-κB activation.

Tetraspanin

A family of transmembrane proteins that have four transmembrane domains and two extracellular domains of different sizes, which are defined by several conserved amino acids in the transmembrane domains. Their function is not fully known, but they seem to interact with many other transmembrane proteins and to form large multimeric protein networks.

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Pillai, S., Cariappa, A. The follicular versus marginal zone B lymphocyte cell fate decision. Nat Rev Immunol 9, 767–777 (2009). https://doi.org/10.1038/nri2656

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