title: Stress-activated Dendritic Cells (DC) Induce Dual Interleukin (IL)-15- and IL1β-mediated Pathways, Which May Elicit CD4+ Memory T Cells and Interferon (IFN)-stimulated Genes.
abstract: The prevailing evidence suggests that immunological memory does not require antigenic re-stimulation but is maintained by low level tonic stimulation. We examined the hypothesis that stress agents contribute to tonic cellular activation and maintain immunological memory. Stimulation of monocyte-derived dendritic cells (DC) with stress agents elicits reactive oxygen species and HSP70. NFκB is activated, which up-regulates membrane-associated (ma) IL-15, caspase-1 and IL-1β. Co-culture of stress-treated DC with mononuclear cells activates IL-15 and IL-1β receptors on CD4(+) T cells, eliciting CD40L, proliferation, and up-regulation of CD45RO(+) memory T cells. The transcription factors Tbet(high) and RORγt are up-regulated, whereas FoxP3 is down-regulated, resulting in enhanced Th1 and Th17 expression and the corresponding cytokines. The interaction between maIL-15 expressed by DC and IL-15R on CD4(+) T cells results in one pathway and the corresponding cells expressing IL-1β and IL1βR as a second pathway. Importantly, inhibition studies with IL-15 antibodies and IL-1βR inhibitor suggest that both pathways may be required for optimum CD4(+) CD45RO(+) memory T cell expression. Type 1 IFN expression in splenic CD11c DC of stress-treated mice demonstrated a significant increase of IFN-α in CD11c CD317(+) and CD8α(+) DC. Analysis of RNA in human CD4(+) memory T cells showed up-regulation of type 1 IFN-stimulated genes and inhibition with histone methyltransferase inhibitor. We suggest the paradigm that stress-induced tonic stimulation might be responsible for the robust persistence of the immune response in vaccination and that epigenetic changes are involved in maintaining CD4(+) T cell memory.
authors.affiliation: Mucosal Immunology Unit, Kings College London, London SE1 1UL, United Kingdom.
authors.forename: Yufei
authors.initials: Y
authors.lastname: Wang
authors.affiliation: MRC, and Asthma UK Centre in Allergic Mechanisms of Asthma, Kings College London, London SE1 1UL, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Lavender
authors.affiliation: MRC, and Asthma UK Centre in Allergic Mechanisms of Asthma, Kings College London, London SE1 1UL, United Kingdom.
authors.forename: Julie
authors.initials: J
authors.lastname: Watson
authors.affiliation: Genomics Centre, Kings College London, London SE1 1UL, United Kingdom.
authors.forename: Matthew
authors.initials: M
authors.lastname: Arno
authors.affiliation: Mucosal Immunology Unit, Kings College London, London SE1 1UL, United Kingdom. Electronic address: Thomas.lehner@kcl.ac.uk.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lehner
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D003713:Dendritic Cells; D005786:Gene Expression Regulation / Q000187:drug effects / Q000276:immunology; D018840:HSP70 Heat-Shock Proteins / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory / Q000187:drug effects / Q000502:physiology*; D007370:Interferon Type I / Q000276:immunology; D019409:Interleukin-15 / Q000276:immunology*; D053583:Interleukin-1beta / Q000276:immunology*; D051379:Mice; D016328:NF-kappa B / Q000276:immunology; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology*; D013154:Spleen / Q000166:cytology / Q000276:immunology; D013312:Stress, Physiological / Q000187:drug effects / Q000276:immunology*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology*; D058504:Th17 Cells / Q000166:cytology / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D018840:HSP70 Heat-Shock Proteins; C569274:IL15 protein, human; C508585:IL1B protein, human; C587672:IL1B protein, mouse; D007370:Interferon Type I; D019409:Interleukin-15; D053583:Interleukin-1beta; D016328:NF-kappa B; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C539900:RORC protein, human
keywords: T helper cells; immunology; inflammasome; stress; transcription factor