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mTOR Inhibition Per Se Induces Nuclear Localization of FOXP3 and Conversion of Invariant NKT (iNKT) Cells into Immunosuppressive Regulatory iNKT Cells.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2015 Sep 01; Vol. 195 (5), pp. 2038-45. Date of Electronic Publication: 2015 Aug 03. - Publication Year :
- 2015
-
Abstract
- CD1d-restricted activation of invariant NKT (iNKT) cells results in the abundant production of various types of cytokines and the subsequent modulation of immune responses. This has been shown to be relevant in several clinical disorders, including cancer, autoimmunity, and graft tolerance. Although it is well known that the suppressive function of regulatory T cells is critically dependent on the FOXP3 gene, FOXP3 can also be expressed by conventional human T cells upon activation, indicating the lack of specificity of FOXP3 as a marker for suppressive cells. In this study, we report that the mammalian target of rapamycin (mTOR) inhibitor rapamycin and IL-10, but not TGF-β, can induce FOXP3 expression in iNKT cell lines. Importantly, however, FOXP3(+) iNKT cells only acquired suppressive abilities when cultured in the presence of the mTOR inhibitor rapamycin. Suppression of responder T cell proliferation by FOXP3(+) iNKT cells was found to be cell contact-dependent and was accompanied by a reduced capacity of iNKT cells to secrete IFN-γ. Notably, imaging flow cytometry analysis demonstrated predominant nuclear localization of FOXP3 in suppressive FOXP3(+) iNKT cells, whereas nonsuppressive FOXP3(+) iNKT cells showed a predominance of cytoplasmically localized FOXP3. In conclusion, whereas IL-10 can enhance FOXP3 expression in iNKT cells, mTOR inhibition is solely required for promoting nuclear localization of FOXP3 and the induction of suppressive FOXP3(+) iNKT cells.<br /> (Copyright © 2015 by The American Association of Immunologists, Inc.)
- Subjects :
- Active Transport, Cell Nucleus drug effects
Active Transport, Cell Nucleus immunology
CTLA-4 Antigen immunology
CTLA-4 Antigen metabolism
Cell Line
Cell Nucleus metabolism
Cell Proliferation drug effects
Cells, Cultured
Dendritic Cells drug effects
Dendritic Cells immunology
Dendritic Cells metabolism
Flow Cytometry
Forkhead Transcription Factors metabolism
Humans
Immunosuppressive Agents immunology
Immunosuppressive Agents pharmacology
Interferon-gamma immunology
Interferon-gamma metabolism
Interleukin-10 immunology
Interleukin-10 pharmacology
Monocytes drug effects
Monocytes immunology
Monocytes metabolism
Natural Killer T-Cells metabolism
Sirolimus immunology
Sirolimus pharmacology
T-Lymphocytes immunology
T-Lymphocytes metabolism
T-Lymphocytes, Regulatory drug effects
T-Lymphocytes, Regulatory immunology
T-Lymphocytes, Regulatory metabolism
TOR Serine-Threonine Kinases antagonists & inhibitors
TOR Serine-Threonine Kinases metabolism
Cell Nucleus immunology
Forkhead Transcription Factors immunology
Natural Killer T-Cells immunology
TOR Serine-Threonine Kinases immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 195
- Issue :
- 5
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 26238486
- Full Text :
- https://doi.org/10.4049/jimmunol.1402710