title: Differential responsiveness to IL-2, IL-7, and IL-15 common receptor gamma chain cytokines by antigen-specific peripheral blood naive or memory cytotoxic CD8+ T cells from healthy donors and melanoma patients.
abstract: Common receptor gamma chain (c-gamma) cytokines (CKs) support proliferation of CD8+ T cells in presence or absence of antigen triggering and help maintaining the immunologic memory. We addressed the effects of low (< or = 5 ng/mL)-dose interleukin (IL)-2, IL-7, or IL-15 on human naive and memory antigen-specific CD8+ T cells. Peripheral blood CD8+ lymphocytes proliferated with decreasing efficiency in response to IL-15, IL-7, and IL-2. Of note, IL-15 preferentially promoted expansion of CD45RA/CD8+ T-cell memory subset. Accordingly, cytotoxic T lymphocytes specific for cytomegalovirus-derived antigens from seropositive donors proliferated in response to IL-15 and, to lesser extent to IL-7, but poorly to IL-2. CD8+ T cells were then pretreated with CK before antigen stimulation using, as read out, specific cytotoxic activity. After the pretreatment with IL-15, but not IL-2, previously experienced viral antigens induced vigorous cytotoxic responses. Minor effects of IL-7 were also detectable. In contrast, IL-2 best supported the cytotoxic T lymphocyte generation from prevailingly naive CD8 T cells from HLA-A*0201 healthy donors, specific for L27Melan-A/MART-126-35 melanoma-associated antigen. Cells from melanoma patients were tested before and after Melan-A/MART-1-targeted antigen-specific immunotherapy. Untreated patients showed heterogeneous patterns of responsiveness to c-gamma CK. However, when naive patients whose CD8+ T cells best responded to IL-2 were vaccinated, a modified responsiveness pattern was detectable. After immunization, cells displayed a significantly higher response to IL-15 than to IL-2 pretreatment. Thus, responsiveness to c-gamma CK is critically influenced by naive or memory status of peripheral blood CD8+ T cells.
authors.affiliation: Institute of Surgical Research and Hospital Management, Department of Biomedicine, University Hospital of Basel, Switzerland.
authors.forename: Rachel
authors.initials: R
authors.lastname: Rosenthal
authors.forename: Célia
authors.initials: C
authors.lastname: Groeper
authors.forename: Laura
authors.initials: L
authors.lastname: Bracci
authors.forename: Michel
authors.initials: M
authors.lastname: Adamina
authors.forename: Chantal
authors.initials: C
authors.lastname: Feder-Mengus
authors.forename: Paul
authors.initials: P
authors.lastname: Zajac
authors.forename: Giandomenica
authors.initials: G
authors.lastname: Iezzi
authors.forename: Martin
authors.initials: M
authors.lastname: Bolli
authors.forename: Walter P
authors.initials: WP
authors.lastname: Weber
authors.forename: Daniel M
authors.initials: DM
authors.lastname: Frey
authors.forename: Urs
authors.initials: U
authors.lastname: von Holzen
authors.forename: Daniel
authors.initials: D
authors.lastname: Oertli
authors.forename: Michael
authors.initials: M
authors.lastname: Heberer
authors.forename: Giulio C
authors.initials: GC
authors.lastname: Spagnoli
mesh_terms: D000956:Antigens, Viral / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007156:Immunologic Memory; D007167:Immunotherapy; D053631:Interleukin Receptor Common gamma Subunit / Q000276:immunology*; D019409:Interleukin-15 / Q000494:pharmacology*; D007376:Interleukin-2 / Q000494:pharmacology*; D015851:Interleukin-7 / Q000494:pharmacology*; D008545:Melanoma / Q000276:immunology*; D010455:Peptides / Q000276:immunology / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology
chemical_list: D000956:Antigens, Viral; D053631:Interleukin Receptor Common gamma Subunit; D019409:Interleukin-15; D007376:Interleukin-2; D015851:Interleukin-7; D010455:Peptides