title: The IL-15 receptor {alpha} chain cytoplasmic domain is critical for normal IL-15Ralpha function but is not required for trans-presentation.
abstract: IL-15 is critical for natural killer (NK)-cell development and function and for memory CD8(+) T-cell homeostasis. The IL-15 receptor consists of IL-15Ralpha, IL-2Rbeta, and the common cytokine receptor gamma chain (gamma(c)). IL-15Ralpha is known to "trans-present" IL-15 to an IL-2Rbeta/gamma(c) heterodimeric receptor on responding cells to initiate signaling. To investigate the importance of the IL-15Ralpha cytoplasmic domain, we generated a chimeric receptor consisting of the extracellular domain of IL-15Ralpha and intracellular domain of IL-2Ralpha (IL-15Ralpha(ext)/IL-2Ralpha(int)) and examined its function in 32D cells, in knock-in (KI) mice, and in adoptive-transfer experiments. The chimeric protein exhibited decreased cell-surface expression, and KI mice exhibited diminished NK, NKT, and CD8(+) T-cell development and defects in T-cell functional responses. However, 32D cells expressing the chimeric receptor had less IL-15-induced proliferation than wild-type (WT) transfectants with similar levels of IL-15Ralpha expression, indicating a signaling role for the IL-15Ralpha cytoplasmic domain beyond its effect on expression, and demonstrating that the IL-2Ralpha and IL-15Ralpha cytoplasmic domains are functionally distinct. Interestingly, adoptive-transfer experiments indicated that the chimeric IL-15Ralpha(ext)/IL-2Ralpha(int) receptor still supports trans-presentation. These experiments collectively indicate that IL-15Ralpha can act in cis in addition to acting in trans to present IL-15 to responding cells.
authors.affiliation: Laboratory of Molecular Immunology, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892-1674, USA.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wu
authors.forename: Hai-Hui
authors.initials: HH
authors.lastname: Xue
authors.forename: Jérôme
authors.initials: J
authors.lastname: Bernard
authors.forename: Rong
authors.initials: R
authors.lastname: Zeng
authors.forename: Dmitry
authors.initials: D
authors.lastname: Issakov
authors.forename: Julie
authors.initials: J
authors.lastname: Bollenbacher-Reilley
authors.forename: Igor M
authors.initials: IM
authors.lastname: Belyakov
authors.forename: Sangkon
authors.initials: S
authors.lastname: Oh
authors.forename: Jay A
authors.initials: JA
authors.lastname: Berzofsky
authors.forename: Warren J
authors.initials: WJ
authors.lastname: Leonard
mesh_terms: D019264:Adoptive Transfer / Q000662:veterinary; D000818:Animals; D017951:Antigen Presentation / Q000502:physiology*; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D003593:Cytoplasm / Q000378:metabolism; D005260:Female; D007371:Interferon-gamma / Q000378:metabolism; D019409:Interleukin-15 / Q000378:metabolism*; D053720:Interleukin-15 Receptor alpha Subunit / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000166:cytology / Q000378:metabolism / Q000502:physiology; D017434:Protein Structure, Tertiary / Q000502:physiology; D014162:Transfection
chemical_list: D019409:Interleukin-15; D053720:Interleukin-15 Receptor alpha Subunit; D007371:Interferon-gamma
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