title: Immune memory-boosting dose of rapamycin impairs macrophage vesicle acidification and curtails glycolysis in effector CD8 cells, impairing defense against acute infections.
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.
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724; Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721; and.
authors.forename: Emily L
authors.initials: EL
authors.lastname: Goldberg
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724;
authors.forename: Megan J
authors.initials: MJ
authors.lastname: Smithey
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724; Department of Molecular and Cellular Biology, College of Science, University of Arizona, Tucson, AZ 85721.
authors.forename: Lydia K
authors.initials: LK
authors.lastname: Lutes
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724;
authors.forename: Jennifer L
authors.initials: JL
authors.lastname: Uhrlaub
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724; Department of Nutritional Sciences, College of Agriculture and Life Sciences, University of Arizona, Tucson, AZ 85721; and nikolich@email.arizona.edu.
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Žugich
mesh_terms: D000328:Adult; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006019:Glycolysis / Q000187:drug effects / Q000276:immunology; D053804:Granzymes / Q000276:immunology / Q000378:metabolism; D054884:Host-Pathogen Interactions / Q000187:drug effects / Q000276:immunology; D006801:Humans; D006863:Hydrogen-Ion Concentration; D007156:Immunologic Memory / Q000276:immunology; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D008089:Listeria monocytogenes / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008088:Listeriosis / Q000276:immunology / Q000382:microbiology / Q000517:prevention & control; D008216:Lymphocytic Choriomeningitis / Q000276:immunology / Q000517:prevention & control / Q000821:virology; D008217:Lymphocytic choriomeningitis virus / Q000187:drug effects / Q000276:immunology / Q000502:physiology; D008247:Lysosomes / Q000737:chemistry / Q000187:drug effects / Q000276:immunology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma; D053804:Granzymes; D020123:Sirolimus