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 3

Effective TCR signaling of αGalCer-pretreated iNKT cells.

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Effective TCR signaling of αGalCer-pretreated iNKT cells. (A and B) Cont...
(A and B) Control Nur77GFP mice and Nur77GFP mice injected 1 month earlier with 4 μg αGalCer (Nur77GFP/αGC) were challenged i.v. with 1 μg αGalCer, and GFP expression by splenic iNKT cells was analyzed 1 hour later. Representative data (A) and a summary graph of the GFP+ cells (B) are shown. αGalCer-pre, αGalCer pretreatment. Expression levels of unstimulated iNKT cells from C57BL/6 (B6) mice are shown in A as a negative control. (C) Enriched splenocytes from control congenic C57BL/6 mice (CD45.1+) and from C57BL/6 mice (CD45.2+) injected 1 month earlier with 4 μg αGalCer (B6/αGC) were mixed and stimulated by cross-linking with αCD3ε antibodies. Two minutes later, cells were fixed, and the expression of p-ERK1/2 by indicated iNKT cells was analyzed. Numbers in the histograms denote the geometric mean values for the depicted antigen in iNKT cells. Representative data from at least 2 independent experiments are shown in each panel.