Abstract
Murine T cells exposed to rapamycin maintain flexibility towards Th1/Tc1 differentiation, thereby indicating that rapamycin promotion of regulatory T cells (Tregs) is conditional. The degree to which rapamycin might inhibit human Th1/Tc1 differentiation has not been evaluated. In the presence of rapamycin, T cell costimulation and polarization with IL-12 or IFN-α permitted human CD4+ and CD8+ T cell differentiation towards a Th1/Tc1 phenotype; activation of STAT1 and STAT4 pathways essential for Th1/Tc1 polarity was preserved during mTOR blockade but instead abrogated by PI3 kinase inhibition. Such rapamycin-resistant human Th1/Tc1 cells: (1) were generated through autophagy (increased LC3BII expression; phenotype reversion by autophagy inhibition via 3-MA or siRNA for Beclin1); (2) expressed anti-apoptotic bcl-2 family members (reduced Bax, Bak; increased phospho-Bad); (3) maintained mitochondrial membrane potentials; and (4) displayed reduced apoptosis. In vivo, type I polarized and rapamycin-resistant human T cells caused increased xenogeneic graft-versus-host disease (x-GVHD). Murine recipients of rapamycin-resistant human Th1/Tc1 cells had: (1) persistent T cell engraftment; (2) increased T cell cytokine and cytolytic effector function; and (3) T cell infiltration of skin, gut, and liver. Rapamycin therefore does not impair human T cell capacity for type I differentiation. Rather, rapamycin yields an anti-apoptotic Th1/Tc1 effector phenotype by promoting autophagy.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Adenine / analogs & derivatives
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Adenine / pharmacology
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Animals
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Apoptosis / drug effects*
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Apoptosis / immunology
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Apoptosis Regulatory Proteins / metabolism
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Autophagy / drug effects*
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Autophagy / immunology
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Beclin-1
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Cell Differentiation / drug effects
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Cell Differentiation / immunology
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Cell Polarity / drug effects
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Cell Polarity / immunology
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Drug Resistance / drug effects
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Gene Knockdown Techniques
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Graft vs Host Disease / immunology*
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Graft vs Host Disease / pathology*
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Humans
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Immunologic Memory / drug effects
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Interferon-alpha / pharmacology
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Interleukin-12 / pharmacology
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Lipopolysaccharides / pharmacology
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Membrane Potential, Mitochondrial / drug effects
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Membrane Proteins / metabolism
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Mice
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Mice, Transgenic
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Phenotype
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Phosphatidylinositol 3-Kinases / metabolism
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Proto-Oncogene Proteins c-bcl-2 / metabolism
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RNA, Small Interfering / metabolism
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STAT Transcription Factors / metabolism
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Sirolimus / pharmacology*
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T-Lymphocytes, Cytotoxic / cytology*
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T-Lymphocytes, Cytotoxic / drug effects
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T-Lymphocytes, Cytotoxic / enzymology
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Th1 Cells / cytology*
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Th1 Cells / drug effects
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Th1 Cells / enzymology
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Tumor Necrosis Factor-alpha / pharmacology
Substances
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Apoptosis Regulatory Proteins
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BECN1 protein, human
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Beclin-1
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Interferon-alpha
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Lipopolysaccharides
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Membrane Proteins
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Proto-Oncogene Proteins c-bcl-2
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RNA, Small Interfering
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STAT Transcription Factors
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Tumor Necrosis Factor-alpha
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Interleukin-12
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3-methyladenine
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Phosphatidylinositol 3-Kinases
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Adenine
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Sirolimus