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PI3K in lymphocyte development, differentiation and activation

Key Points

  • Recent mouse-knockout experiments have indicated crucial, non-redundant functions for individual phosphoinositide 3-kinase (PI3K) subunits.

  • p85α and p110δ have crucial roles in B-cell development, differentiation and function.

  • p110δ, but not p85α, has an important role in T-cell activation and differentiation.

  • p110γ regulates innate immunity and T-cell activation, but it is not clear what extracellular stimuli regulate p110γ in T cells.

  • CD5+ B1 cells and marginal-zone B cells do not develop in the absence of PI3K activity.

  • Recruitment of PI3K by the T-cell co-stimulatory receptor CD28 seems to have a selective role in the regulation of cell survival, but not in proliferation or interleukin-2 production.

  • Unrestrained PI3K signalling, caused by the lack of expression of SH2-domain-containing inositol polyphosphate D5 phosphatase (SHIP) or phosphatase and tensin homologue (PTEN), can lead to autoimmune disease and/or leukaemia.

  • The phenotypes of p110δ- and p110γ-deficient mice indicate that these subunits are attractive drug targets for the alleviation of autoimmune diseases.

Abstract

Phosphoinositide 3-kinases (PI3Ks) regulate numerous biological processes, including cell growth, differentiation, survival, proliferation, migration and metabolism. In the immune system, impaired PI3K signalling leads to immunodeficiency, whereas unrestrained PI3K signalling contributes to autoimmunity and leukaemia. New insights into the role of PI3Ks in lymphocyte biology have been derived from gene-targeting studies, which have identified the PI3K subunits that are involved in B-cell and T-cell signalling. In particular, the catalytic subunit p110δ seems to be adapted to transmit antigen-receptor signalling in B and T cells. Additional recent work has provided new insights into the molecular interactions that lead to PI3K activation and the signalling pathways that are regulated by PI3K.

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Figure 1: Genetic dissection of PI3K signalling in B-cell development.
Figure 2: PI3K activation and signalling in B cells.
Figure 3: PI3K activation and signalling in T cells.
Figure 4: Two modes of CD28-dependent activation of PI3K.

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Acknowledgements

Research in the laboratory of B.V. is supported by the Ludwig Institute for Cancer Research, Diabetes UK, the UK Biotechnology and Biological Sciences Research Council (BBSRC) and the European Union Framework V Programme (QLG1-2001-02171). K.O. has been supported by fellowships from the Ludwig Institute and the European Union Framework V Programme, and is currently a BBSRC David Phillips fellow. We wish to thank the members of the Cell Signalling Group and the collaborators who have contributed to work described in this review.

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DATABASES

LocusLink

AKT/PKB

B7

BAM32

BCAP

BTK

CBL

Cd19

CD28

CD44

CD62L

GADS

ICOS

IL-2

IL-4

IL-10

IL-12

ITK

LAT

LYN

p55γ

p85α

p85β

p101

p110α

p110β

p110γ

p110δ

Pik3r1

PLCγ2

PTEN

RAC

RLK

SHIP

SLP76

TAPP1

TAPP2

TGF-β

TRIM

VAV1

VAV3

Vps34

FURTHER INFORMATION

Bart Vanhaesebroeck's lab homepage

Protein Interaction Domains

Protein Families Database of Alignments and HMMs

Signal Transduction Knowledge Environment

Alliance for Cellular Signalling

Glossary

PHOSPHOINOSITIDE 3-KINASES

(PI3Ks). A family of enzymes that phosphorylate the D3 position of phosphoinositides. The class IA PI3Ks, which are the focus of this review, phosphorylate phosphatidylinositol-(4,5)-bisphosphate to produce phosphatidylinositol-(3,4,5)-trisphosphate.

PHOSPHATIDYLINOSITOL-(4,5)-BISPHOSPHATE

(PtdInsP2). Note that phosphatidylinositol-(3,4)-bisphosphate (resulting from the hydrolysis of PtdInsP3 by SHIP) is sometimes also referred to as PtdInsP2, but this can lead to confusion and should be avoided.

PLECKSTRIN-HOMOLOGY DOMAIN

(PH domain). A non-catalytic modular domain present in more than 180 signalling proteins. Some, but far from all, PH domains bind phosphatidylinositols. Of the proteins described in this review, PDK1, AKT/PKB, BTK, ITK, TEC, BAM32 and the TAPPs contain a signature motif that facilitates binding to PtdInsP3 and/or PtdIns(3,4)P2.

RAG COMPLEMENTATION

Gene-targeted embryonic stem (ES) cells are injected into blastocysts from recombination-activating gene (Rag)-knockout mice and implanted into a pseudopregnant female. Any B or T cells in the resulting chimaeric mouse are derived from the injected ES cells.

RHO-GAP DOMAIN

A protein domain of 200 residues that encodes GTPase-activating protein (GAP) activity for RHO-family members. In p85, this domain is also known as a breakpoint cluster region-homology (BH) domain. It is not clear yet if this domain has RHO-GAP activity in p85.

THYMUS-DEPENDENT ANTIGENS

Antigenic stimuli that require the function of thymus-derived lymphocytes to generate a humoral immune response.

THYMUS-INDEPENDENT ANTIGENS

Antigenic stimuli that promote humoral immune responses in the absence of thymus-derived lymphocytes.

SH2-DOMAIN-CONTAINING INOSITOL POLYPHOSPHATE D5 PHOSPHATASE

(SHIP). A lipid phosphatase that removes the D5 phosphate from PtdInsP3 to yield PtdIns(3,4)P2.

SRC-HOMOLOGY 2 DOMAIN

(SH2 domain). A non-catalytic modular protein domain that binds to phosphotyrosines in specific sequence motifs.

SRC-HOMOLOGY 3 DOMAIN

(SH3 domain). A non-catalytic modular protein domain that binds to proline-rich sequences.

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Okkenhaug, K., Vanhaesebroeck, B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol 3, 317–330 (2003). https://doi.org/10.1038/nri1056

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