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 4

Involvement of IL-12 and MIP-2 in sulfatide-induced recruitment of iNKT cells.

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Involvement of IL-12 and MIP-2 in sulfatide-induced recruitment of iNKT ...
(A) Flow cytometric analysis of liver MNCs isolated at the indicated times from groups of IL-12p40+/+ and IL-12p40–/– mice injected i.p. with 20 μg sulfatide or PBS alone. Groups of IL-12p40+/+ mice also received a neutralizing dose of anti–IL-12 or control IgG1 24 hours before injection with sulfatide. Two-color staining was performed using α-GalCer/CD1d tetramers and anti–TCR-β mAbs. Numbers in quadrants indicate percent positive cells in total liver lymphocytes. (B) Real-time PCR analysis of mRNA isolated from liver tissues at the indicated times after injection in sulfatide- compared with PBS-treated mice. *P < 0.02, **P < 0.009 versus PBS. ConA-stimulated splenocytes were used as a control. (C) Flow cytometric analysis of liver MNCs isolated from groups of C57BL/6 mice injected i.p. with 20 μg sulfatide or PBS alone. Groups of mice also received a neutralizing dose of anti–MIP-2 or control IgG1 24 hours before injection with sulfatide. Analysis was performed as in A. Numbers in quadrants indicate percent positive cells in total liver lymphocytes. (D) Recruitment of iNKT cells into liver following sulfatide injection alone or in combination with anti–IL-12, anti–MIP-2, or isotype-matched IgG1 control antibodies. #P < 0.005 versus sulfatide alone or sulfatide plus IgG1. Data are representative of 3–5 individual experiments.