title: Limiting {gamma}c expression differentially affects signaling via the interleukin (IL)-7 and IL-15 receptors.
abstract: X-linked severe combined immunodeficiency (SCID-X1) results from mutations in the IL2RG gene, which encodes the common gamma chain (gammac) of the receptors for interleukin (IL)-2, 4, 7, 9, 15, and 21. Affected infants typically lack T and natural killer (NK) cells as a consequence of loss of signaling via the IL-7 receptor (IL-7R) and the IL-15R, respectively. In some infants, however, autologous NK cells are observed despite failure of T-cell ontogeny. The mechanisms by which mutations in gammac differentially impact T- and NK-cell ontogeny remain incompletely understood. We used SCID-X1 patient-derived EBV-transformed B cells to test the hypothesis that the IL-15R-mediated signaling is preferentially retained as gammac expression becomes limiting. Signal transduction via the IL-15R was readily detected in control EBV-transformed B cells, and via the IL-7R when modified to express IL-7Ralpha. Under the same experimental conditions, patient-derived EBV-transformed B cells expressing trace amounts of gammac proved incapable of signal transduction via the IL-7R while retaining the capacity for signal transduction via the IL-15R. An equivalent result was obtained in ED-7R cells modified to express varying levels of gammac. Collectively, these results confirm that signal transduction via the IL-15R, and hence NK ontogeny, is preferentially retained relative to the IL-7R as gammac expression becomes limiting.
authors.affiliation: Gene Therapy Research Unit, Children's Medical Research Institute and The Children's Hospital at Westmead, Australia.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Smyth
authors.forename: Samantha L
authors.initials: SL
authors.lastname: Ginn
authors.forename: Claire T
authors.initials: CT
authors.lastname: Deakin
authors.forename: Grant J
authors.initials: GJ
authors.lastname: Logan
authors.forename: Ian E
authors.initials: IE
authors.lastname: Alexander
mesh_terms: D001402:B-Lymphocytes / Q000378:metabolism*; D016022:Case-Control Studies; D002461:Cell Line, Transformed; D004854:Herpesvirus 4, Human; D006801:Humans; D007223:Infant; D053631:Interleukin Receptor Common gamma Subunit / Q000096:biosynthesis / Q000502:physiology*; D053720:Interleukin-15 Receptor alpha Subunit / Q000378:metabolism*; D015851:Interleukin-7 / Q000378:metabolism*; D007694:Killer Cells, Natural / Q000378:metabolism*; D010766:Phosphorylation; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D053632:X-Linked Combined Immunodeficiency Diseases / Q000276:immunology*
chemical_list: C508605:IL7 protein, human; D053631:Interleukin Receptor Common gamma Subunit; D053720:Interleukin-15 Receptor alpha Subunit; D015851:Interleukin-7; D050799:STAT5 Transcription Factor