Inactivation of PI3Kgamma and PI3Kdelta distorts T-cell development and causes multiple organ inflammation.
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.
Ji
Hong
H
Merck Serono S. A., Geneva Research Center, Geneva, Switzerland. hong.ji@merckserono.net
Rintelen
Felix
F
Waltzinger
Caroline
C
Bertschy Meier
Dominique
D
Bilancio
Antonio
A
Pearce
Wayne
W
Hirsch
Emilio
E
Wymann
Matthias P
MP
Rückle
Thomas
T
Camps
Montserrat
M
Vanhaesebroeck
Bart
B
Okkenhaug
Klaus
K
Rommel
Christian
C
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
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