Type II NKT cell–mediated anergy induction in type I NKT cells prevents inflammatory liver disease
Ramesh C. Halder, Carlos Aguilera, Igor Maricic, Vipin Kumar
Ramesh C. Halder, Carlos Aguilera, Igor Maricic, Vipin Kumar
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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 5

Anergy induction in the iNKT population.

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Anergy induction in the iNKT population. (A) Tri-color flow cytometric p...
(A) Tri-color flow cytometric profiles of liver MNCs isolated 3 hours following sulfatide, α-GalCer, or PBS injection. CD69 expression in α-GalCer/CD1d tetramer+ or tetramer– populations is shown. Numbers above brackets indicate MFI; numbers below brackets indicate percent positive cells. (B) IFN-γ+α-GalCer/CD1d tetramer+ cells in total liver lymphocytes at the indicated times following sulfatide, α-GalCer, or PBS injection. (C) Incorporation of [3H]-thymidine in triplicate cultures of splenocytes in response to in vitro challenge with α-GalCer (10 ng/ml) in the absence or presence of IL-2 (5 ng/ml). Splenocytes were isolated from mice 3 and 12 hours after sulfatide injection.*P < 0.002, **P < 0.001 versus 0 hours. (D) CFSE dilution profile of α-GalCer/CD1d tetramer+ (iNKT) cells in splenocytes isolated at the indicated time points from sulfatide- or PBS-injected mice. Splenocytes were labeled with CFSE and stimulated with α-GalCer in vitro in the presence or absence of IL-2. IL-12 served as a control. (E) CFSE dilution analysis of hepatic α-GalCer/CD1d tetramer+ cells in response to in vitro stimulation with α-GalCer from IL-12p40+/+ and IL-12p40–/– mice injected with sulfatide or PBS. Numbers above brackets in D and E indicate percent positive cells. Data are representative of 3–4 individual experiments.