Impaired B and T Cell Antigen Receptor Signaling in p110δ PI 3-Kinase Mutant Mice

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: p110α, p110β, and p110δ. It is unclear to what extent these p110 isoforms have overlapping or distinct biological roles. Mice expressing a catalytically inactive form of p110δ (p110δD910A) were generated by gene targeting. Antigen receptor signaling in B and T cells was impaired and immune responses in vivo were attenuated in p110δ mutant mice. They also developed inflammatory bowel disease. These results reveal a selective role for p110δ in immunity.

[1]  J. Sprent,et al.  T cell memory. , 2003, Annual review of immunology.

[2]  J. Penninger,et al.  Phosphoinositide 3-kinases in immunity: lessons from knockout mice. , 2002, Journal of biochemistry.

[3]  L. Cantley,et al.  Phosphoinositide 3-kinase in immunological systems. , 2002, Seminars in immunology.

[4]  F. Powrie,et al.  Regulatory T cells in the control of immune pathology , 2001, Nature Immunology.

[5]  Peter Ebert,et al.  Immature CD4+CD8+ Thymocytes Do Not Polarize Lipid Rafts in Response to TCR-Mediated Signals1 , 2000, The Journal of Immunology.

[6]  L. Cantley,et al.  Impaired Kit- but Not FcεRI-initiated Mast Cell Activation in the Absence of Phosphoinositide 3-Kinase p85α Gene Products* , 2000, The Journal of Biological Chemistry.

[7]  R. Nussbaum,et al.  Proliferative Defect and Embryonic Lethality in Mice Homozygous for a Deletion in the p110α Subunit of Phosphoinositide 3-Kinase* , 1999, The Journal of Biological Chemistry.

[8]  A. Lanzavecchia,et al.  T lymphocyte costimulation mediated by reorganization of membrane microdomains. , 1999, Science.

[9]  J. Kinet,et al.  PtdIns-3,4,5-P3 A Regulatory Nexus between Tyrosine Kinases and Sustained Calcium Signals , 1998, Cell.

[10]  L. Cantley,et al.  Conditional Inhibition of the Mitogen-activated Protein Kinase Cascade by Wortmannin , 1997, The Journal of Biological Chemistry.

[11]  A. Heimberger,et al.  Induction by antigen of intrathymic apoptosis of CD4+CD8+TCRlo thymocytes in vivo. , 1990, Science.