title: IL-15 can signal via IL-15Rα, JNK, and NF-κB to drive RANTES production by myeloid cells.
abstract: IL-15 plays many important roles within the immune system. IL-15 signals in lymphocytes via trans presentation, where accessory cells such as macrophages and dendritic cells present IL-15 bound to IL-15Rα in trans to NK cells and CD8(+) memory T cells expressing IL-15/IL-2Rβ and common γ chain (γ(c)). Previously, we showed that the prophylactic delivery of IL-15 to Rag2(-/-)γ(c)(-/-) mice (mature T, B, and NK cell negative) afforded protection against a lethal HSV-2 challenge and metastasis of B16/F10 melanoma cells. In this study, we demonstrated that in vivo delivery of an adenoviral construct optimized for the secretion of human IL-15 to Rag2(-/-)γ(c)(-/-) mice resulted in significant increases in spleen size and cell number, leading us to hypothesize that IL-15 signals differently in myeloid immune cells compared with lymphocytes, for which IL-15/IL-2Rβ and γ(c) expression are essential. Furthermore, treatment with IL-15 induced RANTES production by Rag2(-/-)γ(c)(-/-) bone marrow cells, but the presence of γ(c) did not increase bone marrow cell sensitivity to IL-15. This IL-15-mediated RANTES production by Rag2(-/-)γ(c)(-/-) bone marrow cells occurred independently of the IL-15/IL-2Rβ and Jak/STAT pathways and instead required IL-15Rα signaling as well as activation of JNK and NF-κB. Importantly, we also showed that the trans presentation of IL-15 by IL-15Rα boosts IL-15-mediated IFN-γ production by NK cells but reduces IL-15-mediated RANTES production by Rag2(-/-)γ(c)(-/-) myeloid bone marrow cells. Our data clearly show that IL-15 signaling in NK cells is different from that of myeloid immune cells. Additional insights into IL-15 biology may lead to novel therapies aimed at bolstering targeted immune responses against cancer and infectious disease.
authors.affiliation: Department of Pathology and Molecular Medicine, McMaster Immunology Research Centre and Institute for Infectious Disease Research, McMaster University, Hamilton, Ontario L8S 4K1, Canada.
authors.forename: Meghan J
authors.initials: MJ
authors.lastname: Chenoweth
authors.forename: M Firoz
authors.initials: MF
authors.lastname: Mian
authors.forename: Nicole G
authors.initials: NG
authors.lastname: Barra
authors.forename: Tommy
authors.initials: T
authors.lastname: Alain
authors.forename: Nahum
authors.initials: N
authors.lastname: Sonenberg
authors.forename: Jonathan
authors.initials: J
authors.lastname: Bramson
authors.forename: Brian D
authors.initials: BD
authors.lastname: Lichty
authors.forename: Carl D
authors.initials: CD
authors.lastname: Richards
authors.forename: Averil
authors.initials: A
authors.lastname: Ma
authors.forename: Ali A
authors.initials: AA
authors.lastname: Ashkar
mesh_terms: D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D018946:Chemokine CCL5 / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory / Q000502:physiology; D007239:Infections / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D019409:Interleukin-15 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053720:Interleukin-15 Receptor alpha Subunit / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053646:Interleukin-2 Receptor beta Subunit / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D016328:NF-kappa B / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D009928:Organ Specificity; D050791:STAT Transcription Factors / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
chemical_list: C483024:CCL5 protein, human; C503460:Ccl5 protein, mouse; D018946:Chemokine CCL5; D004268:DNA-Binding Proteins; C569274:IL15 protein, human; C508022:Il2rb protein, mouse; D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D053646:Interleukin-2 Receptor beta Subunit; D016328:NF-kappa B; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; D050791:STAT Transcription Factors; D048670:MAP Kinase Kinase 4