Back to Search
Start Over
Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections.
- Source :
-
Journal of immunology (Baltimore, Md. : 1950) [J Immunol] 2014 Jul 15; Vol. 193 (2), pp. 757-63. Date of Electronic Publication: 2014 Jun 09. - Publication Year :
- 2014
-
Abstract
- Direct mammalian target of rapamycin (Rapa) complex 1 inhibition by short-term low-dose Rapa treatment has recently been shown to improve CD8 T cell immunological memory. Whereas these studies focused on memory development, the impact of low-dose Rapa on the primary immune response, particularly as it relates to functional effector immunity, is far less clear. In this study, we investigated the impact of acute Rapa treatment on immune effector cell function during the primary immune response to several acute infections. We found that functional CD8 T cell and macrophage responses to both viral and intracellular bacterial pathogens were depressed in mice in vivo and in humans to phorbol ester and calcium ionophore stimulation in vitro in the face of low-dose Rapa treatment. Mechanistically, the CD8 defect was linked to impaired glycolytic switch in stimulated naive cells and the reduced formation of short-lived effector cells. Therefore, more than one cell type required for a protective effector immune response is impaired by Rapa in both mice and humans, at the dose shown to improve immune memory and extend lifespan. This urges caution with regard to the relative therapeutic costs and benefits of Rapa treatment as means to improve immune memory.<br /> (Copyright © 2014 by The American Association of Immunologists, Inc.)
- Subjects :
- Adult
Animals
CD8-Positive T-Lymphocytes immunology
CD8-Positive T-Lymphocytes metabolism
Cells, Cultured
Dose-Response Relationship, Drug
Flow Cytometry
Glycolysis drug effects
Glycolysis immunology
Granzymes immunology
Granzymes metabolism
Host-Pathogen Interactions drug effects
Host-Pathogen Interactions immunology
Humans
Hydrogen-Ion Concentration
Immunologic Memory immunology
Immunosuppressive Agents pharmacology
Interferon-gamma immunology
Interferon-gamma metabolism
Listeria monocytogenes drug effects
Listeria monocytogenes immunology
Listeria monocytogenes physiology
Listeriosis immunology
Listeriosis microbiology
Listeriosis prevention & control
Lymphocytic Choriomeningitis immunology
Lymphocytic Choriomeningitis prevention & control
Lymphocytic Choriomeningitis virology
Lymphocytic choriomeningitis virus drug effects
Lymphocytic choriomeningitis virus immunology
Lymphocytic choriomeningitis virus physiology
Lysosomes chemistry
Lysosomes drug effects
Lysosomes immunology
Macrophages immunology
Macrophages metabolism
Mice
Mice, Inbred C57BL
T-Lymphocyte Subsets immunology
T-Lymphocyte Subsets metabolism
Tumor Necrosis Factor-alpha immunology
Tumor Necrosis Factor-alpha metabolism
CD8-Positive T-Lymphocytes drug effects
Macrophages drug effects
Sirolimus pharmacology
T-Lymphocyte Subsets drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1550-6606
- Volume :
- 193
- Issue :
- 2
- Database :
- MEDLINE
- Journal :
- Journal of immunology (Baltimore, Md. : 1950)
- Publication Type :
- Academic Journal
- Accession number :
- 24913978
- Full Text :
- https://doi.org/10.4049/jimmunol.1400188