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 1

Activation of type II NKT cells and cytokine secretion following sulfatide injection.

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Activation of type II NKT cells and cytokine secretion following sulfati...
(A) Flow cytometric profile of liver MNCs isolated at the indicated times from groups of C57BL/6 mice (n = 2 per group) injected i.p. with 20 μg sulfatide (Sulf), 2 μg α-GalCer (α-Gal), or PBS alone. Two-color staining was performed using sulfatide/CD1d tetramers and anti–TCR-β. Numbers within boxes indicate percent positive cells in total liver lymphocytes. (B) Tri-color flow cytometric analysis of IFN-γ+ cells in liver 3 hours after sulfatide injection. IFN-γ+ cells in sulfatide/CD1d tetramer+ (Tet+) or tetramer– cells are shown. Numbers above brackets indicate percent positive cells. (C) ELISPOT analysis of splenocytes isolated at the indicated times from CD1d+/+, CD1d–/–, or Jα18–/– mice following injection with sulfatide or PBS. *P < 0.002. (D) Serum cytokine levels in CD1d+/+ and CD1d–/– mice were examined at the indicated time points following sulfatide or α-GalCer injection. Values are mean ± SD. Data are representative of 3–4 individual experiments.