title: Low-affinity TCR engagement drives IL-2-dependent post-thymic maintenance of naive CD4+ T cells in aged humans.
abstract: Insight into the maintenance of naive T cells is essential to understand defective immune responses in the context of aging and other immune compromised states. In humans, naive CD4+ T cells, in contrast to CD8+ T cells, are remarkably well retained with aging. Here, we show that low-affinity TCR engagement is the main driving force behind the emergence and accumulation of naive-like CD4+ T cells with enhanced sensitivity to IL-2 in aged humans. In vitro, we show that these CD45RA(+) CD25(dim) CD4(+) T cells can develop from conventional naive CD25(-) CD4+ T cells upon CD3 cross-linking alone, in the absence of costimulation, rather than via stimulation by the homeostatic cytokines IL-2, IL-7, or IL-15. In vivo, TCR engagement likely occurs in secondary lymphoid organs as these cells were detected in lymph nodes and spleen where they showed signs of recent activation. CD45RA(+) CD25(dim) CD4+ T cells expressed a broad TCRVβ repertoire and could readily differentiate into functional T helper cells. Strikingly, no expansion of CD45RA(+) CD25(dim) CD8+ T cells was detected with aging, thereby implying that maintenance of naive CD4+ T cells is uniquely regulated. Our data provide novel insight into the homeostasis of naive T cells and may guide the development of therapies to preserve or restore immunity in the elderly.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Kornelis S M
authors.initials: KS
authors.lastname: van der Geest
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Wayel H
authors.initials: WH
authors.lastname: Abdulahad
authors.affiliation: Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Nato
authors.initials: N
authors.lastname: Teteloshvili
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Sarah M
authors.initials: SM
authors.lastname: Tete
authors.affiliation: Department of Laboratory Medicine - Medical Immunology, Radboud University Medical Centre, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Jorieke H
authors.initials: JH
authors.lastname: Peters
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Gerda
authors.initials: G
authors.lastname: Horst
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Pedro G
authors.initials: PG
authors.lastname: Lorencetti
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Nicolaas A
authors.initials: NA
authors.lastname: Bos
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Annechien
authors.initials: A
authors.lastname: Lambeck
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Caroline
authors.initials: C
authors.lastname: Roozendaal
authors.affiliation: Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Bart-Jan
authors.initials: BJ
authors.lastname: Kroesen
authors.affiliation: Department of Laboratory Medicine - Medical Immunology, Radboud University Medical Centre, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Hans J P M
authors.initials: HJ
authors.lastname: Koenen
authors.affiliation: Department of Laboratory Medicine - Medical Immunology, Radboud University Medical Centre, Postbus 9101, 6500 HB, Nijmegen, The Netherlands.
authors.forename: Irma
authors.initials: I
authors.lastname: Joosten
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Brouwer
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands.
authors.forename: Annemieke M H
authors.initials: AM
authors.lastname: Boots
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000375:Aging / Q000097:blood / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002478:Cells, Cultured; D003430:Cross-Sectional Studies; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology*; D008875:Middle Aged; D011948:Receptors, Antigen, T-Cell / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology* / Q000276:immunology*; D055815:Young Adult
chemical_list: D007376:Interleukin-2; D011948:Receptors, Antigen, T-Cell
keywords: T lymphocytes; TCR engagement; aging; homeostasis; interleukin-2; interleukin-7