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Science 297 (5583): 1031-1034

Copyright © 2002 by the American Association for the Advancement of Science

Impaired B and T Cell Antigen Receptor Signaling in p110&dgr; PI 3-Kinase Mutant Mice

Klaus Okkenhaug,1 Antonio Bilancio,1* Géraldine Farjot,1* Helen Priddle,2*dagger Sara Sancho,3 Emma Peskett,1 Wayne Pearce,1 Stephen E. Meek,2 Ashreena Salpekar,1 Michael D. Waterfield,14 Andrew J. H. Smith,2 Bart Vanhaesebroeck14ddagger

Class IA phosphoinositide 3-kinases (PI3Ks) are a family of p85/p110 heterodimeric lipid kinases that generate second messenger signals downstream of tyrosine kinases, thereby controlling cell metabolism, growth, proliferation, differentiation, motility, and survival. Mammals express three class IA catalytic subunits: p110alpha , p110beta , and p110delta . It is unclear to what extent these p110 isoforms have overlapping or distinct biological roles. Mice expressing a catalytically inactive form of p110delta (p110delta D910A) were generated by gene targeting. Antigen receptor signaling in B and T cells was impaired and immune responses in vivo were attenuated in p110delta mutant mice. They also developed inflammatory bowel disease. These results reveal a selective role for p110delta in immunity.

1 Ludwig Institute for Cancer Research, 91 Riding House Street, London W1W 7BS, UK.
2 Gene Targeting Laboratory, Center for Genome Research, University of Edinburgh, West Mains Road, Edinburgh, EH9 3JQ, UK.
3 Frimorfo, Rue du Musée 12, CH-1705 Fribourg, Switzerland.
4 Department of Biochemistry and Molecular Biology, University College London, Gower Street, London WC1E 6BT, UK.
*   These authors contributed equally to this report.

dagger    Present address: Roslin Institute, Roslin, Midlothian, EH25 9PS, UK.

ddagger    To whom correspondence should be addressed. E-mail: bartvanh{at}ludwig.ucl.ac.uk



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The p110{gamma} isoform of phosphatidylinositol 3-kinase regulates migration of effector CD4 T lymphocytes into peripheral inflammatory sites.
M. S. Thomas, J. S. Mitchell, C. C. DeNucci, A. L. Martin, and Y. Shimizu (2008)
J. Leukoc. Biol. 84, 814-823
   Abstract »    Full Text »    PDF »
Phosphatidylinositol 3-kinase signaling in mammalian preimplantation embryo development.
C. O'Neill (2008)
Reproduction 136, 147-156
   Abstract »    Full Text »    PDF »
Regulation of integrin activation through the B-cell receptor.
E. Arana, N. E. Harwood, and F. D. Batista (2008)
J. Cell Sci. 121, 2279-2286
   Abstract »    Full Text »    PDF »
The p110{beta} isoform of phosphoinositide 3-kinase signals downstream of G protein-coupled receptors and is functionally redundant with p110{gamma}.
J. Guillermet-Guibert, K. Bjorklof, A. Salpekar, C. Gonella, F. Ramadani, A. Bilancio, S. Meek, A. J. H. Smith, K. Okkenhaug, and B. Vanhaesebroeck (2008)
PNAS 105, 8292-8297
   Abstract »    Full Text »    PDF »
T cell receptor signaling controls Foxp3 expression via PI3K, Akt, and mTOR.
S. Sauer, L. Bruno, A. Hertweck, D. Finlay, M. Leleu, M. Spivakov, Z. A. Knight, B. S. Cobb, D. Cantrell, E. O'Connor, et al. (2008)
PNAS 105, 7797-7802
   Abstract »    Full Text »    PDF »
Science amongst the vines: Meeting on Signalling Systems.
S. M. Pitson, G. J. Goodall, and M. A. Guthridge (2008)
EMBO Rep. 9, 425-428
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Interleukin 13 Increases Contractility of Murine Tracheal Smooth Muscle by a Phosphoinositide 3-kinase p110{delta}-Dependent Mechanism.
H. S. M. Farghaly, I. S. Blagbrough, D. A. Medina-Tato, and M. L. Watson (2008)
Mol. Pharmacol. 73, 1530-1537
   Abstract »    Full Text »    PDF »
Phosphoinositide 3-Kinases p110{alpha} and p110{beta} Regulate Cell Cycle Entry, Exhibiting Distinct Activation Kinetics in G1 Phase.
M. Marques, A. Kumar, I. Cortes, A. Gonzalez-Garcia, C. Hernandez, M. C. Moreno-Ortiz, and A. C. Carrera (2008)
Mol. Cell. Biol. 28, 2803-2814
   Abstract »    Full Text »    PDF »
PI3K is a negative regulator of IgE production.
T. Doi, K. Obayashi, T. Kadowaki, H. Fujii, and S. Koyasu (2008)
Int. Immunol. 20, 499-508
   Abstract »    Full Text »    PDF »
CD38 induces differentiation of immature transitional 2 B lymphocytes in the spleen.
J. C. Rodriguez-Alba, M. E. Moreno-Garcia, C. Sandoval-Montes, V. H. Rosales-Garcia, and L. Santos-Argumedo (2008)
Blood 111, 3644-3652
   Abstract »    Full Text »    PDF »
Selective Regulation of CD8 Effector T Cell Migration by the p110{gamma} Isoform of Phosphatidylinositol 3-Kinase.
A. L. Martin, M. D. Schwartz, S. C. Jameson, and Y. Shimizu (2008)
J. Immunol. 180, 2081-2088
   Abstract »    Full Text »    PDF »
Isoform-Specific Functions of Phosphoinositide 3-Kinases: p110{delta} but Not p110{gamma} Promotes Optimal Allergic Responses In Vivo.
K. Ali, M. Camps, W. P. Pearce, H. Ji, T. Ruckle, N. Kuehn, C. Pasquali, C. Chabert, C. Rommel, and B. Vanhaesebroeck (2008)
J. Immunol. 180, 2538-2544
   Abstract »    Full Text »    PDF »
Phosphoinositide Lipid Phosphatases: Natural Regulators of Phosphoinositide 3-Kinase Signaling in T Lymphocytes.
S. J. Harris, R. V. Parry, J. Westwick, and S. G. Ward (2008)
J. Biol. Chem. 283, 2465-2469
   Abstract »    Full Text »    PDF »
CD28 provides T-cell costimulation and enhances PI3K activity at the immune synapse independently of its capacity to interact with the p85/p110 heterodimer.
F. Garcon, D. T. Patton, J. L. Emery, E. Hirsch, R. Rottapel, T. Sasaki, and K. Okkenhaug (2008)
Blood 111, 1464-1471
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The Effect of Deleting p110{delta} on the Phenotype and Function of PTEN-Deficient B Cells.
M. L. Janas, D. Hodson, Z. Stamataki, S. Hill, K. Welch, L. Gambardella, L. C. Trotman, P. P. Pandolfi, E. Vigorito, and M. Turner (2008)
J. Immunol. 180, 739-746
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Protein kinase B (c-akt) regulates hematopoietic lineage choice decisions during myelopoiesis.
M. Buitenhuis, L. P. Verhagen, H. W. M. van Deutekom, A. Castor, S. Verploegen, L. Koenderman, S.-E. W. Jacobsen, and P. J. Coffer (2008)
Blood 111, 112-121
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Endothelial PI 3-kinase activity regulates lymphocyte diapedesis.
M. Nakhaei-Nejad, A. M. Hussain, Q.-X. Zhang, and A. G. Murray (2007)
Am J Physiol Heart Circ Physiol 293, H3608-H3616
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Phosphoinositide 3 kinase {gamma} participates in T cell receptor induced T cell activation.
I. Alcazar, M. Marques, A. Kumar, E. Hirsch, M. Wymann, A. C. Carrera, and D. F. Barber (2007)
J. Exp. Med. 204, 2977-2987
   Abstract »    Full Text »    PDF »

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