title: Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.
abstract: Mice lacking both the p110gamma and p110delta isoforms display severe impairment of thymocyte development. Here, we show that this phenotype is recapitulated in p110gamma-/-/p110delta(D910A/D910A) (p110gamma(KO)delta(D910A)) mice where the p110delta isoform has been inactivated by a point mutation. Moreover, we have examined the pathological consequences of the p110gammadelta deficiency, which include profound T-cell lymphopenia, T-cell and eosinophil infiltration of mucosal organs, elevated IgE levels, and a skewing toward Th2 immune responses. Using small-molecule selective inhibitors, we demonstrated that in mature T cells, p110delta, but not p110gamma, controls Th1 and Th2 cytokine secretion. Thus, the pathology in the p110gammadelta-deficient mice is likely to be secondary to a developmental block in the thymus that leads to lymphopenia-associated inflammatory responses.
authors.affiliation: Merck Serono S. A., Geneva Research Center, Geneva, Switzerland. hong.ji@merckserono.net
authors.forename: Hong
authors.initials: H
authors.lastname: Ji
authors.forename: Felix
authors.initials: F
authors.lastname: Rintelen
authors.forename: Caroline
authors.initials: C
authors.lastname: Waltzinger
authors.forename: Dominique
authors.initials: D
authors.lastname: Bertschy Meier
authors.forename: Antonio
authors.initials: A
authors.lastname: Bilancio
authors.forename: Wayne
authors.initials: W
authors.lastname: Pearce
authors.forename: Emilio
authors.initials: E
authors.lastname: Hirsch
authors.forename: Matthias P
authors.initials: MP
authors.lastname: Wymann
authors.forename: Thomas
authors.initials: T
authors.lastname: Rückle
authors.forename: Montserrat
authors.initials: M
authors.lastname: Camps
authors.forename: Bart
authors.initials: B
authors.lastname: Vanhaesebroeck
authors.forename: Klaus
authors.initials: K
authors.lastname: Okkenhaug
authors.forename: Christian
authors.initials: C
authors.lastname: Rommel
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016207:Cytokines / Q000096:biosynthesis; D004797:Enzyme-Linked Immunosorbent Assay; D004804:Eosinophils / Q000378:metabolism; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D007070:Immunoglobulin A / Q000097:blood; D007073:Immunoglobulin E / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007075:Immunoglobulin M / Q000097:blood; D007249:Inflammation / Q000209:etiology / Q000276:immunology*; D007527:Isoenzymes / Q000172:deficiency / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D008231:Lymphopenia / Q000209:etiology; D051379:Mice; D008817:Mice, Mutant Strains; D009092:Mucous Membrane / Q000276:immunology / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000172:deficiency* / Q000276:immunology; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D013270:Stomach / Q000276:immunology / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology; D018418:Th2 Cells / Q000166:cytology* / Q000276:immunology*; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology
chemical_list: D058534:Class I Phosphatidylinositol 3-Kinases; D058544:Class Ib Phosphatidylinositol 3-Kinase; D016207:Cytokines; D007070:Immunoglobulin A; D007073:Immunoglobulin E; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D007527:Isoenzymes; D019869:Phosphatidylinositol 3-Kinases; C421683:Pik3cd protein, mouse; C546764:Pik3cg protein, mouse