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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Cell Proliferation
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Class I Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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Cytokines / biosynthesis
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Enzyme-Linked Immunosorbent Assay
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Eosinophils / metabolism
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Flow Cytometry
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Fluorescent Antibody Technique
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Immunoglobulin A / blood
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Immunoglobulin E / blood
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Immunoglobulin G / blood
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Immunoglobulin M / blood
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Inflammation / etiology
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Inflammation / immunology*
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Isoenzymes / deficiency
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Isoenzymes / immunology
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Lymphocyte Culture Test, Mixed
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Lymphopenia / etiology
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Mice
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Mice, Mutant Strains
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Mucous Membrane / immunology
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Mucous Membrane / pathology
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Phosphatidylinositol 3-Kinases / deficiency*
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Phosphatidylinositol 3-Kinases / immunology
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Salivary Glands / immunology
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Salivary Glands / pathology
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Stomach / immunology
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Stomach / pathology
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T-Lymphocyte Subsets / cytology
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T-Lymphocyte Subsets / immunology
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Th2 Cells / cytology*
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Th2 Cells / immunology*
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Thymus Gland / immunology
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Thymus Gland / pathology
Substances
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Cytokines
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Immunoglobulin A
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Immunoglobulin G
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Immunoglobulin M
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Isoenzymes
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Immunoglobulin E
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Class I Phosphatidylinositol 3-Kinases
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Class Ib Phosphatidylinositol 3-Kinase
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Pik3cd protein, mouse
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Pik3cg protein, mouse