The Interactions of Multiple Cytokines Control NK Cell Maturation

Brady, J; Carotta, S; Thong, RPL; Chan, CJ; Hayakawa, Y; Smyth, MJ; Nutt, SL

Author(s): Brady, J; Carotta, S; Thong, RPL; Chan, CJ; Hayakawa, Y; Smyth, MJ; Nutt, SL;
Details: Publication Year 2010-12-01,Volume 185,Issue #11,Page 6679-6688
Journal Title: JOURNAL OF IMMUNOLOGY
Publication Type: Journal Article
Abstract: Although NK cells are well known for their cytotoxic functions, they also produce an array of immunoregulatory cytokines and chemokines. During an immune response, NK cells are exposed to complex combinations of cytokines that influence their differentiation and function. In this study, we have examined the phenotypic and functional consequences of exposing mouse NK cells to IL-4, IL-12, IL-15, IL-18, and IL-21 and found that although all factors induced signs of maturation, characterized by decreased proliferation and IFN-gamma secretion, distinct combinations induced unique cytokine secretion profiles. In contrast, the immunosuppressive factors IL-10 and TGF-beta had little direct effect on NK cell effector functions. Sustained IL-18 signals resulted in IL-13 and GM-CSF production, whereas IL-12 and IL-21 induced IL-10 and TNF-alpha. Surprisingly, with the exception of IL-21, all cytokines suppressed cytotoxic function of NK cells at the expense of endogenous cytokine production suggesting that "helper-type" NK cells were generated. The cytokine signals also profoundly altered the cell surface phenotype of the NK cells-a striking example being the downregulation of the activating receptor NKG2D by IL-4 that resulted in decreased NKG2D-dependent killing. IL-4 exposure also modulated NKG2D expression in vivo suggesting it is functionally important during immune responses. This study highlights the plasticity of NK cell differentiation and suggests that the relative abundance of cytokines at sites of inflammation will lead to diverse outcomes in terms of NK cell phenotype and interaction with the immune system. The Journal of Immunology, 2010, 185: 6679-6688.
Publisher: AMER ASSOC IMMUNOLOGISTS
Keywords: NATURAL-KILLER-CELLS; IFN-GAMMA PRODUCTION; T-CELLS; IN-VIVO; DENDRITIC CELLS; CUTTING EDGE; HELPER-CELLS; DIFFERENTIATION; EXPRESSION; RECEPTOR
Publisher's Version: https://doi.org/10.4049/jimmunol.0903354
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2010-12-01 12:00:00