IL-21 induces the functional maturation of murine NK cells.
IL-21 is a recently identified cytokine that stimulates mouse NK cell effector functions in vitro. In this study we demonstrate that IL-21 achieves its stimulatory effect by inducing the development of mature NK cells into a large granular lymphocyte phenotype with heightened effector function. IL-21 treatment results in increased cell size and granularity and a corresponding decrease in cell viability and proliferative potential. These cells up-regulate the expression of the inhibitory CD94-NKG2A receptor complex and the activation markers CD154 and killer cell, lectin-like-receptor G1. Surprisingly, IL-21 treatment also results in down-regulation of the pan-NK marker, NK1.1. Coinciding with these cellular changes IL-21 enhances cytolytic capacity across a spectrum of target sensitivities and induces IL-10 and IFN-gamma production. In vivo treatment with IL-21 results in a very similar activation and phenotypic maturation of NK cells as well as a potent increase in NK cell-mediated anti-tumor immunity that is perforin dependent. These developmental changes suggested that IL-21 functions to induce the terminal differentiation of mouse NK cells, resulting in heightened NK cell-mediated cytotoxicity and immune surveillance.
Brady
Jason
J
The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Hayakawa
Yoshihiro
Y
Smyth
Mark J
MJ
Nutt
Stephen L
SL
D000818:Animals; D000941:Antigens / Q000096:biosynthesis; D000950:Antigens, Ly; D000954:Antigens, Surface; D015415:Biomarkers / Q000032:analysis; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D015536:Down-Regulation / Q000276:immunology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000502:physiology; D016130:Immunophenotyping; D019409:Interleukin-15 / Q000502:physiology; D007376:Interleukin-2 / Q000502:physiology; D007378:Interleukins / Q000008:administration & dosage / Q000502:physiology*; D007694:Killer Cells, Natural / Q000166:cytology* / Q000276:immunology* / Q000378:metabolism; D037181:Lectins, C-Type; D008113:Liver Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008213:Lymphocyte Activation / Q000276:immunology; D016131:Lymphocyte Subsets / Q000276:immunology / Q000378:metabolism; D008546:Melanoma, Experimental / Q000276:immunology / Q000517:prevention & control / Q000556:secondary; D008562:Membrane Glycoproteins / Q000172:deficiency / Q000235:genetics / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D055651:NK Cell Lectin-Like Receptor Subfamily B; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D014176:Protein Biosynthesis; D011506:Proteins / Q000037:antagonists & inhibitors; D000098546:Interleukin-21
D000941:Antigens; D000950:Antigens, Ly; D000954:Antigens, Surface; D015415:Biomarkers; D016207:Cytokines; D006131:Growth Inhibitors; D019409:Interleukin-15; D007376:Interleukin-2; D007378:Interleukins; C527211:Klrb1c protein, mouse; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D055651:NK Cell Lectin-Like Receptor Subfamily B; D052899:Pore Forming Cytotoxic Proteins; D011506:Proteins; D054353:Perforin; D000098546:Interleukin-21