Type II NKT cell–mediated anergy induction in type I NKT cells prevents inflammatory liver disease
Ramesh C. Halder, … , Igor Maricic, Vipin Kumar
Ramesh C. Halder, … , Igor Maricic, Vipin Kumar
Published August 1, 2007
Citation Information: J Clin Invest. 2007;117(8):2302-2312. https://doi.org/10.1172/JCI31602.
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Research Article

Type II NKT cell–mediated anergy induction in type I NKT cells prevents inflammatory liver disease

Abstract

Because of the paucity of known self lipid–reactive ligands for NKT cells, interactions among distinct NKT cell subsets as well as immune consequences following recognition of self glycolipids have not previously been investigated. Here we examined cellular interactions and subsequent immune regulatory mechanism following recognition of sulfatide, a self-glycolipid ligand for a subset of CD1d-restricted type II NKT cells. Using glycolipid/CD1d tetramers and cytokine responses, we showed that activation of sulfatide-reactive type II NKT cells and plasmacytoid DCs caused IL-12– and MIP-2–dependent recruitment of type I, or invariant, NKT (iNKT) cells into mouse livers. These recruited iNKT cells were anergic and prevented concanavalin A–induced (ConA-induced) hepatitis by specifically blocking effector pathways, including the cytokine burst and neutrophil recruitment that follow ConA injection. Hepatic DCs from IL-12+/+ mice, but not IL-12–/– mice, adoptively transferred anergy in recipients; thus, IL-12 secretion by DCs enables them to induce anergy in iNKT cells. Our data reveal what we believe to be a novel mechanism in which interactions among type II NKT cells and hepatic DCs result in regulation of iNKT cell activity that can be exploited for intervention in inflammatory diseases, including autoimmunity and asthma.

Authors

Ramesh C. Halder, Carlos Aguilera, Igor Maricic, Vipin Kumar

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Figure 2

Selective activation of hepatic pDCs following sulfatide recognition.

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Selective activation of hepatic pDCs following sulfatide recognition. (A...
(A) Flow cytometric analysis of hepatic pDCs (B220+CD11c+) 3 hours following sulfatide, α-GalCer, or PBS injection. Dot plots are gated on whole MNCs; histogram plots are gated CD11cint and CD11chi populations. Numbers within plots and above brackets indicate percent positive cells. (B) Flow cytometric analysis of costimulatory molecules on hepatic purified CD11c+DCs 12 hours following sulfatide, α-GalCer, or PBS injection. Gated populations were analyzed for anti–I-Ab (class II), anti-CD80 (B7.1), anti-CD86 (B7.2), and anti-CD40. Histogram plots are gated on B220+CD11cint (pDC) or CD11b+CD11chi (mDC) populations. The marker was set up using isotype-matched control Ab. Numbers above brackets indicate MFI; numbers below brackets indicate percent positive cells. (C) Percent change in MFI of CD1d expression on pDCs and mDCs 12 hours following sulfatide or α-GalCer injections in comparison to PBS-injected group. (D) MFI of IL-12 cytokine secreted by hepatic purified CD11c+ DCs 3 hours following sulfatide injection. *P < 0.002. (E) Tri-color flow cytometric analysis of pDCs isolated from sulfatide-injected mice as in B. Liver MNCs were stained with allophycocyanin-conjugated anti–mouse PDCA-1 and PE-conjugated CD11c. Numbers above brackets indicate MFI; numbers below brackets and within plots indicate percent positive cells. Data are representative of 2–3 individual experiments.