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Calcium signalling and cell-fate choice in B cells

Nature Reviews Immunology volume 7, pages 778–789 (2007)Cite this article

Key Points

  • B cells receive information that is crucial to their physiology and function through cytosolic Ca2+ signals, one of the most important of which is produced by the B-cell receptor (BCR).

  • The BCR Ca2+ signal is initiated by inositol-1,4,5-trisphosphate (InsP3) produced by phospholipase Cγ2 (PLCγ2), which is activated through a positive-feedback loop. If InsP3 accumulates to a threshold required to maintain endoplasmic reticulum Ca2+ store depletion, activation of store-operated Ca2+ entry (SOCE) leads to a sustained Ca2+ signal.

  • The sensitivity of positive-feedback-loop-mediated activation of PLCγ2 to either augmenting or inhibitory influences renders the amplitude and duration of the Ca2+ signal subject to regulation over a wide dynamic range.

  • Microenvironmental cues may indirectly influence B-cell cytosolic Ca2+ concentration through contributions to the total pool of activated PLC and InsP3, or through direct effects on Ca2+ fluxes mediated by transporters or channels.

  • One potentially important but often overlooked mechanism for direct regulation of Ca2+ fluxes is membrane potential. Differential K+-channel expression in B-cell subsets and newly discovered monovalent selective ion channels of the transient receptor potential melastatin related (TRPM) family provide new mechanisms for dynamic regulation of membrane potential in B cells.

  • Future work will be challenged to integrate the panoply of potential Ca2+ regulatory mechanisms with present models of how Ca2+-dependent signals regulate cell-fate choice in distinct immunological contexts.

Abstract

Alterations in the cytosolic concentration of calcium ions (Ca2+) transmit information that is crucial for the development and function of B cells. Cytosolic Ca2+ concentration is determined by a balance of active transport and gradient-driven Ca2+ fluxes, both of which are subject to the influence of multiple receptors and environmental sensing pathways. Recent advances in genomics have allowed for the compilation of an increasingly comprehensive list of Ca2+ transporters and channels expressed by B cells. The increasing understanding of the function and regulation of these proteins has begun to shift the frontier of Ca2+ physiology in B cells from molecular analysis to determining how diverse inputs to cytosolic Ca2+ concentration are integrated in specific immunological contexts.

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Figure 1: Ca2+ physiology in B cells in a resting state and during InsP3-mediated Ca2+ signals.
Figure 2: Biochemical events in a B-cell receptor signalling complex leading to amplified PLCγ2 activation.
Figure 3: Cell-surface-receptor mechanisms for modulation of BCR-induced Ca2+ signals.
Figure 4: Mechanisms for the regulation of cytosolic Ca2+ in B cells.
Figure 5: Membrane potential modulation of Ca2+ signals.
Figure 6: Potential mechanisms for Ca2+-dependent modulation of B-cell fate determination.

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Acknowledgements

Our work is supported by the National Institutes of Health (NIH) grants AI45901, GM64316 and GM64091 to A.M.S., and CA81140, HD37091, HL07543, AI044259 and a Leukemia/Lymphoma Society award to D.J.R. We apologize to any colleagues whose work we have overlooked, or whose work we were not able to cite due to space limitations.

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  1. Departments of Pediatrics and Immunology, University of Washington School of Medicine and Children's Hospital and Regional Medical Center, Suite 300, 307 Westlake Avenue, Seattle, 98109, Washington, USA

    Andrew M. Scharenberg, Lisa A. Humphries & David J. Rawlings

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  1. Andrew M. Scharenberg
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  2. Lisa A. Humphries
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Correspondence to Andrew M. Scharenberg or David J. Rawlings.

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Supplementary information S1 (table)

Modulatory inputs to InsP3–dependent Ca2+ release (PDF 248 kb)

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Glossary

Conformational coupling

The regulation of ion-channel gating by interaction with another protein, as opposed to gating through changes in plasma-membrane potential or interaction with a diffusible second messenger.

Reverse mode Na+/Ca2+ exchange

The major physiological role for Na+/Ca2+ exchange channels is thought to be the removal of Ca2+ from the cytosol in exchange for extracellular Na+. If ionic conditions in the microenvironment of an exchange channel are appropriate, it is possible for the exchange channel to operate in reverse and exchange intracellular Na+ for extracellular Ca2+ — this is referred to as reverse mode exchange.

Germinal centres

Located in peripheral lymphoid tissues (for example, the spleen or lymph nodes), these structures are sites of B-cell proliferation and selection for clones that produce antigen-specific antibodies of higher affinity.

Somatic hypermutation

A unique mutation mechanism that is targeted to the variable regions of rearranged immunoglobulin gene segments. Combined with selection for B cells that produce high-affinity antibody, somatic hypermutation leads to the affinity maturation of B cells in germinal centres.

TEC-kinase family

A third class of protein-tyrosine kinases that is required for the activation of haematopoietic cells — the first and second classes being the SRC- and SYK (spleen tyrosine kinase)-family kinases. The TEC-family kinase prototypes are ITK (interleukin-2-inducible T-cell kinase) in T cells and BTK (Bruton's tyrosine kinase) in B cells. Among other functions, TEC kinases have a crucial role in the activation of phospholipase C enzymes after immunoreceptor ligation.

Marginal-zone B cells

A static, mature B-cell subset that is enriched mainly in the marginal zone of the spleen, which is located at the border of the white pulp.

Membrane potential

The charge difference (measured in mV) between the two surfaces of a biological membrane that arises from the different concentrations of ions such as H+, Na+ or K+ on either side. The Na+/K+-ATPase creates a membrane potential by using the energy stored in ATP to maintain a low concentration of Na+ and a high concentration of K+ in the cell, against a higher concentration of Na+ and a lower concentration of K+ on the outside.

Channel conductance

Conductance is defined as current divided by voltage, and in biological systems this means the current flowing across a biological membrane divided by the electrical potential across that membrane. When used in reference to a single open ion channel (single channel conductance) it provides a measure of the amount of current a single open ion channel can carry. Single channel conductance is usually independent of plasma membrane potential, and thus characteristic of that particular ion channel. Individual ion channels with small single channel conductances carry less current at a given membrane potential than those with large single channel conductances.

Voltage-operated channels

Plasma-membrane ion channels the gating of which is regulated by changes in plasma membrane potential.

Stretch-activated ion channels

Plasma membrane ion channels the gating of which is regulated by changes in plasma membrane 'stretch' — that is, forces that are directed within or in parallel to the plane of the plasma membrane.

Eicosanoids

Eicosanoids are fatty-acid derivatives, mainly derived from arachidonic-acid precursors, that have a wide variety of biological activities. There are four main classes of eicosanoid — the prostaglandins, prostacyclins, thromboxanes and leukotrienes — derived from the activities of cyclooxygenases and lipoxygenases on membrane-associated fatty-acid precursors.

Non-selective cation channels

Ion channels that exhibit significant selectivity towards a single type of cation are generally designated according to that ionic selectivity — for example, K+ channel or Ca2+ channels. Cation channels which exhibit little selectivity between monovalent cations, or between monovalent cations and one or more divalent cations such as Ca2+ or Mg2+, are typically grouped together and referred to as non-selective cation channels.

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Scharenberg, A., Humphries, L. & Rawlings, D. Calcium signalling and cell-fate choice in B cells. Nat Rev Immunol 7, 778–789 (2007). https://doi.org/10.1038/nri2172

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