title: Interleukin-21 administration to aged mice rejuvenates their peripheral T-cell pool by triggering de novo thymopoiesis.
abstract: The vaccination efficacy in the elderly is significantly reduced compared to younger populations due to thymic involution and age-related intrinsic changes affecting their naïve T-cell compartment. Interleukin (IL)-21 was recently shown to display thymostimulatory properties. Therefore, we hypothesized that its administration to ageing hosts may improve T-cell output and thus restore a competent peripheral T-cell compartment. Indeed, an increase in the production of recent thymic emigrants (RTEs) attributable to intrathymic expansion of early thymic progenitors (ETPs), double-negative (DN), and double-positive (DP) thymocytes as well as thymic epithelial cell (TEC) was observed in recombinant (r)IL-21-treated aged mice. In sharp contrast, no alterations in the frequency of bone marrow (BM)-derived progenitors were detected following rIL-21 administration. Enhanced production of naïve T cells improved the T-cell receptor (TCR) repertoire diversity and re-established a pool of T cells exhibiting higher levels of miR-181a and diminished amounts of the TCR-inhibiting phosphatases SHP-2 and DUSP5/6. As a result, stimulation of T cells derived from rIL-21-treated aged mice displayed enhanced activation of Lck, ZAP-70, and ERK, which ultimately boosted their IL-2 production, CD25 expression, and proliferation capabilities in comparison with T cells derived from control aged mice. Consequently, aged rIL-21-treated mice vaccinated using a tyrosinase-related protein 2 (Trp2)-derived peptide exhibited a substantial delay in B16 tumor growth and improved survival. The results of this study highlight the immunorestorative function of rIL-21 paving its use as a strategy for the re-establishment of effective immunity in the elderly.
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, QC, H3C 1J7, Canada.
authors.forename: E
authors.initials: E
authors.lastname: Al-Chami
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, QC, H3C 1J7, Canada.
authors.forename: A
authors.initials: A
authors.lastname: Tormo
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, QC, H3C 1J7, Canada.
authors.forename: S
authors.initials: S
authors.lastname: Pasquin
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, QC, H3C 1J7, Canada.
authors.forename: R
authors.initials: R
authors.lastname: Kanjarawi
authors.affiliation: Université Paris-Sud, Faculté de Pharmacie, 5 rue J.B. Clément, 92296, Châtenay-Malabry Cedex, France.
authors.forename: S
authors.initials: S
authors.lastname: Ziouani
authors.affiliation: Department of Pharmacology, Université de Montréal, Montréal, QC, H3C 1J7, Canada.
authors.forename: M
authors.initials: M
authors.lastname: Rafei
mesh_terms: D000375:Aging / Q000187:drug effects* / Q000276:immunology; D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D007378:Interleukins / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000187:drug effects* / Q000276:immunology; D060168:Thymocytes / Q000187:drug effects / Q000276:immunology; D013950:Thymus Gland / Q000187:drug effects* / Q000276:immunology; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D011948:Receptors, Antigen, T-Cell; D000098546:Interleukin-21
keywords: T cells; interleukin-21; miR-181a; signaling; thymic involution; tumor vaccine