IL-10–producing NKT10 cells are a distinct regulatory invariant NKT cell subset
Duygu Sag, … , Mitchell Kronenberg, Gerhard Wingender
Duygu Sag, … , Mitchell Kronenberg, Gerhard Wingender
Published July 25, 2014
Citation Information: J Clin Invest. 2014;124(9):3725-3740. https://doi.org/10.1172/JCI72308.
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Research Article Immunology

IL-10–producing NKT10 cells are a distinct regulatory invariant NKT cell subset

Abstract

Invariant natural killer T (iNKT) cells rapidly produce copious amounts of multiple cytokines after activation, thereby impacting a wide variety of different immune reactions. However, strong activation of iNKT cells with α-galactosylceramide (αGalCer) reportedly induces a hyporeactive state that resembles anergy. In contrast, we determined here that iNKT cells from mice pretreated with αGalCer retain cytotoxic activity and maintain the ability to respond to TCR-dependent as well as TCR-independent cytokine-mediated stimulation. Additionally, αGalCer-pretreated iNKT cells acquired characteristics of regulatory cells, including production and secretion of the immunomodulatory cytokine IL-10. Through the production of IL-10, αGalCer-pretreated iNKT cells impaired antitumor responses and reduced disease in experimental autoimmune encephalomyelitis, a mouse model of autoimmune disease. Furthermore, a subset of iNKT cells with a similar inhibitory phenotype and function were present in mice not exposed to αGalCer and were enriched in mouse adipose tissue and detectable in human PBMCs. These data demonstrate that IL-10–producing iNKT cells with regulatory potential (NKT10 cells) represent a distinct iNKT cell subset.

Authors

Duygu Sag, Petra Krause, Catherine C. Hedrick, Mitchell Kronenberg, Gerhard Wingender

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Figure 8

IL-10–dependent immune regulation by induced NKT10 cells.

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IL-10–dependent immune regulation by induced NKT10 cells. (A) C57BL/6 an...
(A) C57BL/6 and Il10–/– mice, either untreated (αGalCer-pre: No) or injected 1 month earlier with 4 μg αGalCer (αGalCer-pre: Yes), were i.v. injected with 1 × 105 B16 melanoma cells. The indicated mice were additionally challenged i.v. 3 times (days 0, 4, and 7) with 1 μg αGalCer (αGalCer: +). Fourteen days later, the number of metastatic nodules in the lung was counted. P < 0.001 for bars 3 and 4 versus bars 7 and 8. Graph summarizes the results from 4 independent experiments with at least 15 mice per group. (B) Jα18–/– mice left untreated (Jα18–/– control) or injected with 5 × 106 splenic iNKT cells enriched from either C57BL/6 (Jα18–/– + WT cells) or Il10–/– mice (Jα18–/– + Il10–/– cells). These mice and the C57BL/6 control mice were then challenged with MOG-CFA and pertussis toxin to induce EAE. Furthermore, all mice were treated 3 times i.v. with αGalCer (days 0, 4, and 7), and disease progression was scored on the indicated days (5–8 mice/group). Experimental outline is depicted in Supplemental Figure 11. The difference between groups was significant (P < 0.05) on the following days: Jα18–/– control versus Jα18–/– + WT cells = day 10 onward (except days 13 and 14); Jα18–/– + WT cells versus Jα18–/– + Il10–/– cells = day 10 onward. Data shown are representative of 2 independent experiments.