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Distinct Effects of Dexamethasone on Human Natural Killer Cell Responses Dependent on Cytokines.

ABSTRACT: Glucocorticoids (GCs) have long been known to be immune suppressive and synthetic variants are widely used in the treatment of inflammatory disorders. Here, we report that, while suppressing the initial production of interferon-γ (IFN-γ), the synthetic GC dexamethasone (Dex) enhances the proliferation and survival of natural killer (NK) cells stimulated with interleukin-2 (IL-2) + interleukin-12 (IL-12). Inhibition of mTOR complex 1 by rapamycin revealed the immunosuppressive activity of Dex was independent from the effect of enhancing NK cell proliferation. In the presence of IL-2 + IL-12, Dex also increased the percentage of NK cells that were CD16⁺ and DNAM1^bright, increased the level of expression of CD94 or NKG2A, and improved mitochondrial function of NK cells. Moreover, NK cells treated with cytokines IL-2 and IL-12 + Dex, followed by a 7-day rest, displayed an increased IFN-γ response upon restimulation. Thus, there is a dichotomic effect of GCs on NK cell function dependent on the local cytokine milieu; the NK cell effector response is initially suppressed, but, dependent on the cytokines present, Dex can also augment the proliferation, survival, and reactivity of human NK cells in a secondary recall response.

SUBMITTER: Morgan DJ

PROVIDER: S-EPMC5389971 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundHuman CD1d-restricted, invariant natural killer T cells (iNKT) are a unique class of T lymphocytes that recognise glycolipid antigens such as alpha-galactosylceramide (alphaGalCer) and upon T cell receptor (TCR) activation produce both Th1 and Th2 cytokines. iNKT cells expand when cultured in-vitro with alphaGalCer and interleukin 2 (IL-2) in a CD1d-restricted manner. However, the expansion ratio of human iNKT cells varies between individuals and this has implications for attempts to manipulate this pathway therapeutically. We have studied a panel of twenty five healthy human donors to assess the variability in their in-vitro iNKT cell expansion responses to stimulation with CD1d ligands and investigated some of the factors that may influence this phenomenon.ResultsAlthough all donors had comparable numbers of circulating iNKT cells their growth rates in-vitro over 14 days in response to a range of CD1d ligands and IL-2 were highly donor-dependent. Two reproducible donor response patterns of iNKT expansion were seen which we have called 'strong' or 'poor' iNKT responders. Donor response phenotype did not correlate with age, gender, frequency of circulating iNKT, or with the CD1d ligand utilised. Addition of exogenous recombinant human interleukin 4 (IL-4) to 'poor' responder donor cultures significantly increased their iNKT proliferative capacity, but not to levels equivalent to that of 'strong' responder donors. However in 'strong' responder donors, addition of IL-4 to their cultures did not significantly alter the frequency of iNKT cells in the expanded CD3+ population.Conclusion(i) in-vitro expansion of human iNKT cells in response to CD1d ligand activation is highly donor variable, (ii) two reproducible patterns of donor iNKT expansion were observed, which could be classified into 'strong' and 'poor' responder phenotypes, (iii) donor iNKT response phenotypes did not correlate with age, gender, frequency of circulating iNKT cells, or with the CD1d ligand utilised, (iv) addition of IL-4 to 'poor' but not 'strong' responder donor cultures significantly increased their in-vitro iNKT cell expansion to alphaGalCer.

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Distinct Effects of Dexamethasone on Human Natural Killer Cell Responses Dependent on Cytokines.

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