Analysis of the costimulatory role of IL-2 and IL-15 in initiating proliferation of resting (CD56dim) human NK cells.
IL-15 is a newly described cytokine produced by monocytes and other non-T cells that utilizes the IL-2R beta- and common gamma-chains, thereby stimulating many NK cell functions previously ascribed to IL-2. Thus, IL-15 may promote NK cell activity during innate immune responses, before the activation of T lymphocytes and subsequent production of IL-2. This study investigated the ability of rIL-15 to substitute for rIL-2 in initiating proliferation of resting human NK cells cocultured with various stimulator cells. NK cell proliferation could not be initiated with rIL-15 as the sole costimulatory cytokine. However, NK cell proliferation was initiated with rIL-15 and either rIL-10 or rIL-12, cytokines also produced by monocytes and other APC and implicated in innate immune responses. Individually, rIL-10, rIL-12, and rIL-15 are effective initiators of NK cell proliferation when combined with submitogenic concentrations of rIL-2, indicating their potential involvement in NK cell proliferation at early stages of an Ag-specific T cell immune response. NK cells proliferating in the different cytokine combinations or optimum concentrations of rIL-2 were indistinguishable in terms of phenotype and cytotoxic activity, but differed in whether they secreted IFN-gamma or IL-5. IFN-gamma was secreted in cultures containing rIL-12, whereas IL-5 secretion was dependent upon interaction of IL-2 with the high affinity IL-2R. These results support the notion that NK cell proliferation occurs at different phases of the immune response with the particular cytokine milieu influencing the repertoire of NK cell-secreted cytokines.
Warren
H S
HS
Cancer Research Unit, Woden Valley Hospital, Canberra, Australia.
Kinnear
B F
BF
Kastelein
R L
RL
Lanier
L L
LL
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D004357:Drug Synergism; D006133:Growth Substances / Q000494:pharmacology; D006801:Humans; D016753:Interleukin-10 / Q000494:pharmacology; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15; D007376:Interleukin-2 / Q000494:pharmacology*; D007378:Interleukins / Q000494:pharmacology*; D007399:Interphase / Q000187:drug effects / Q000276:immunology*; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008213:Lymphocyte Activation / Q000187:drug effects*; D011994:Recombinant Proteins / Q000494:pharmacology
D000276:Adjuvants, Immunologic; D006133:Growth Substances; D019409:Interleukin-15; D007376:Interleukin-2; D007378:Interleukins; D011994:Recombinant Proteins; D016753:Interleukin-10; D018664:Interleukin-12