Rapamycin generates anti-apoptotic human Th1/Tc1 cells via autophagy for induction of xenogeneic GVHD.
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.
Amarnath
Shoba
S
Experimental Transplantation and Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA. samarnath@mail.nih.gov
Flomerfelt
Francis A
FA
Costanzo
Carliann M
CM
Foley
Jason E
JE
Mariotti
Jacopo
J
Konecki
Daniel M
DM
Gangopadhyay
Anu
A
Eckhaus
Michael
M
Wong
Susan
S
Levine
Bruce L
BL
June
Carl H
CH
Fowler
Daniel H
DH
D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects* / Q000276:immunology; D000071186:Beclin-1; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D016764:Cell Polarity / Q000187:drug effects / Q000276:immunology; D004351:Drug Resistance / Q000187:drug effects; D055785:Gene Knockdown Techniques; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects; D016898:Interferon-alpha / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D050791:STAT Transcription Factors / Q000378:metabolism; D020123:Sirolimus / Q000494:pharmacology*; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D018417:Th1 Cells / Q000166:cytology* / Q000187:drug effects / Q000201:enzymology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology
D051017:Apoptosis Regulatory Proteins; C491997:BECN1 protein, human; D000071186:Beclin-1; D016898:Interferon-alpha; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D034741:RNA, Small Interfering; D050791:STAT Transcription Factors; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; C025946:3-methyladenine; D019869:Phosphatidylinositol 3-Kinases; D000225:Adenine; D020123:Sirolimus
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