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Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections.

Authors :
Goldberg EL
Smithey MJ
Lutes LK
Uhrlaub JL
Nikolich-Žugich J
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.)

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