title: Effect of IL-7 Therapy on Naive and Memory T Cell Homeostasis in Aged Rhesus Macaques.
abstract: Aging is associated with gradual deterioration of adaptive immune function, a hallmark of which is the profound loss of naive T cells (TN) associated with decline in thymic output and export of new cells into the peripheral T cell pool. Because the lymphotropic cytokine IL-7 plays crucial roles in both development of TN in the thymus and TN homeostasis in the periphery, we sought to determine the extent to which therapeutic administration of IL-7 could reverse TN deficiency in aging rhesus macaques (RM), either by enhancement of the demonstrably reduced thymopoiesis or by peripheral TN expansion. Our results indicate that treatment of both adult (8-15 y) and old (>20 y) RM with recombinant simian IL-7 (rsIL-7) results in only transient increases in peripheral CD4(+) and CD8(+) TN numbers with no long-term benefit, even with repeated therapy. This transient effect was due to peripheral TN expansion and not enhanced thymic function, and appeared to be limited by induction of IL-7 nonresponsiveness. However, rsIL-7 therapy had a more promising effect on the central memory T cell (TCM) population (both CD4(+) and CD8(+)) in adult and old RM, doubling the numbers of these cells in circulation and maintaining this larger population long term. IL-7 therapy did not reduce TCR diversity of the memory T cell compartment, suggesting that rsIL-7-induced expansion was symmetrical. Thus, although rsIL-7 failed to counter age-associated TN loss, the ability of this therapy to expand clonotypically diverse CD4(+) and CD8(+) TCM populations might potentially improve adaptive immune responsiveness in the elderly.
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Afam A
authors.initials: AA
authors.lastname: Okoye
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Mukta
authors.initials: M
authors.lastname: Rohankhedkar
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Audrie L
authors.initials: AL
authors.lastname: Konfe
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Chike O
authors.initials: CO
authors.lastname: Abana
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Matthew D
authors.initials: MD
authors.lastname: Reyes
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Clock
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Derick M
authors.initials: DM
authors.lastname: Duell
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Andrew W
authors.initials: AW
authors.lastname: Sylwester
authors.affiliation: Bio5 Institute, University of Arizona, Tucson, AZ 85721;
authors.forename: Partha
authors.initials: P
authors.lastname: Sammader
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Alfred W
authors.initials: AW
authors.lastname: Legasse
authors.affiliation: Division of Biostatistics, Department of Public Health and Preventive Medicine, Oregon Health & Science University, Portland, OR 97239;
authors.forename: Byung S
authors.initials: BS
authors.lastname: Park
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006;
authors.forename: Michael K
authors.initials: MK
authors.lastname: Axthelm
authors.affiliation: Department of Immunobiology, University of Arizona College of Medicine, Tucson, AZ 85724; and The Arizona Center on Aging, University of Arizona College of Medicine, Tucson, AZ 85724. pickerl@ohsu.edu jnikolich@medadmin.arizona.edu.
authors.forename: Janko
authors.initials: J
authors.lastname: Nikolich-Žugich
authors.affiliation: Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR 97006; Oregon National Primate Research Center, Beaverton, OR 97006; pickerl@ohsu.edu jnikolich@medadmin.arizona.edu.
authors.forename: Louis J
authors.initials: LJ
authors.lastname: Picker
mesh_terms: D000367:Age Factors; D000375:Aging / Q000276:immunology*; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D005434:Flow Cytometry; D006706:Homeostasis / Q000187:drug effects / Q000276:immunology*; D007156:Immunologic Memory / Q000276:immunology*; D015851:Interleukin-7 / Q000276:immunology* / Q000494:pharmacology; D018655:Lymphocyte Count; D008253:Macaca mulatta / Q000276:immunology*; D008297:Male; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D013934:Thymectomy; D013950:Thymus Gland / Q000166:cytology / Q000276:immunology / Q000601:surgery
chemical_list: D015851:Interleukin-7; D011948:Receptors, Antigen, T-Cell