Abstract
This study was designed to determine the role of CD25(+)CD4(+) regulatory T (Tr) cells in CTL maturation and effector functions using a murine CTL line and in vitro MLC. Tr cells inhibited CTL functional maturation, but had no effect on CTL effector functions. In CD4(+) responder T cell-depleted MLC supplemented with IL-2, Tr cells suppressed mature CTL generation only when added within the first 2 days of culture. Tr cells down-regulated levels of active Akt, but not STAT5 or ZAP70 in Ag-primed immature CTLs. Down-regulation of active Akt was accompanied by a reduction in CTL cell size and IL-2Ralpha expression. In Tr cell-depleted MLC, CTLs were generated that exhibited high levels of nonspecific cytotoxicity. Our in vitro findings suggest that Tr cells regulate functional CTL maturation to generate optimal Ag-specific immune responses through the control of the PI3K/Akt pathway.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Antigens / immunology*
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Cell Differentiation / immunology
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Cell Line, Tumor
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Cell Size
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Cytotoxicity, Immunologic / immunology
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DNA-Binding Proteins / biosynthesis
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Dose-Response Relationship, Immunologic
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Down-Regulation / immunology
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Interleukin-2 / pharmacology
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Lymphocyte Culture Test, Mixed / methods
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Lymphocyte Depletion
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Mice
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Mice, Inbred A
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Milk Proteins / biosynthesis
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Phosphatidylinositol 3-Kinases / physiology*
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Phosphoinositide-3 Kinase Inhibitors
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Protein Serine-Threonine Kinases / antagonists & inhibitors
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Protein Serine-Threonine Kinases / biosynthesis
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Protein Serine-Threonine Kinases / physiology*
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Protein-Tyrosine Kinases / biosynthesis
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Proto-Oncogene Proteins / antagonists & inhibitors
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Proto-Oncogene Proteins / biosynthesis
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Proto-Oncogene Proteins / physiology*
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Proto-Oncogene Proteins c-akt
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Receptors, Interleukin-2 / antagonists & inhibitors
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Receptors, Interleukin-2 / biosynthesis*
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STAT5 Transcription Factor
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Signal Transduction / immunology*
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T-Lymphocytes, Cytotoxic / cytology*
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T-Lymphocytes, Cytotoxic / enzymology
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T-Lymphocytes, Cytotoxic / immunology*
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T-Lymphocytes, Regulatory / cytology
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T-Lymphocytes, Regulatory / enzymology
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T-Lymphocytes, Regulatory / immunology*
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Trans-Activators / biosynthesis
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ZAP-70 Protein-Tyrosine Kinase
Substances
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Antigens
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DNA-Binding Proteins
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Interleukin-2
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Milk Proteins
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Phosphoinositide-3 Kinase Inhibitors
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Proto-Oncogene Proteins
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Receptors, Interleukin-2
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STAT5 Transcription Factor
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Trans-Activators
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Protein-Tyrosine Kinases
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ZAP-70 Protein-Tyrosine Kinase
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Zap70 protein, mouse
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Protein Serine-Threonine Kinases
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Proto-Oncogene Proteins c-akt