IL-10–producing NKT10 cells are a distinct regulatory invariant NKT cell subset
Duygu Sag, Petra Krause, Catherine C. Hedrick, Mitchell Kronenberg, Gerhard Wingender
Duygu Sag, Petra Krause, Catherine C. Hedrick, Mitchell Kronenberg, Gerhard Wingender
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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 4

Cytokines activate αGalCer-pretreated iNKT cells.

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Cytokines activate αGalCer-pretreated iNKT cells. (A and B) LPS (40 μg) ...
(A and B) LPS (40 μg) was i.v. injected, as indicated, into C57BL/6 control (B6) mice or mice i.v. injected 1 month earlier with 4 μg αGalCer (B6/αGC) (3 mice/group). Animals were sacrificed after 6 hours, and splenic iNKT cells were analyzed for CD69 expression (P < 0.001 for B6 vs. B6/αGalCer; A), and IFN-γ expression was measured by intracellular cytokine staining (P = 0.345; B). Increase in CD69 expression based on geometric mean values. (C) αGalCer (1 μg) was i.v. injected into wild-type mice (B6), mice i.v. injected 6 weeks earlier with 4 μg αGalCer (B6 αGC), or mice i.v. injected 6 weeks earlier with 4 μg αGalCer and 2 weeks earlier with 40 μg i.v. LPS (B6/αGC + LPS) (3 mice/group). Splenic iNKT cells were analyzed 90 minutes later by intracellular cytokine staining for production of the indicated cytokines. P > 0.5 for B6/αGC versus B6/αGC/LPS for all 3 cytokines. Experimental outline is depicted in Supplemental Figure 2. Representative data from at least 2 independent experiments are shown in each panel.