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Type I IFN-Producing CD4 V14i NKT Cells Facilitate Priming of IL-10-Producing CD8 T Cells by Hepatocytes¹

Department of Internal Medicine I, University of Ulm, Ulm, Germany

Upon entering the liver CD8 T cells encounter large numbers of NKT cells patrolling the hepatocyte (HC) surface facing the perisinusoidal space. We asked whether hepatic NKT cells modulate the priming of CD8 T cells by HC. Hepatic (-galactosyl-ceramide-loaded CD1d dimer binding) NKT cells produce predominantly IL-4 when stimulated with glycolipid-presenting HC but predominantly IFN- when stimulated with glycolipid-presenting dendritic cells. These NKT cells prime naive CD8 T cells to a (K^b-presented) peptide ligand if they simultaneously recognize a CD1d-binding glycolipid presented to them on the surface of the responding CD8 T cells that they prime. No IL-10-producing CD8 T cells are detected if these T cells are primed by either HC or NKT cells. In contrast, IL-10 is produced by HC-primed CD8 T cells if IFN--producing NKT cells are coactivated by the same HC presenting a glycolipid (in the context of CD1d) and an antigenic peptide (in the context of K^b). Hence, IL-10-producing CD8 T cells are generated in a type I IFN-dependent manner if the three cell types (CD8 T cells, NKT cells, and ligand-presenting HC) specifically and closely interact. IL-10-producing CD8 T cells generated under these conditions down-modulate IL-2 (and proliferative) responses of naive CD4 or CD8 T cells primed by DC. If in close proximity, NKT cells can thus locally modulate the phenotype of CD8 T cells during their priming by HC thereby limiting the local activation of proinflammatory immune effector cells and protecting the liver against immune injury.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was supported by Deutsche Forschungsgemeinschaft (DFG) Grant Rei 549/10-2 (to J.R.).

² Address correspondence and reprint requests to Dr. Jörg Reimann, Department of Internal Medicine I, University of Ulm, Albert Einstein Allee 11, Ulm, Germany. E-mail address: joerg.reimann{at}uni-ulm.de

³ Abbreviations used in this paper: V14i, invariant V14; GalCer, -galactosyl-ceramide; BTLA, B and T lymphocyte attenuator; DC, dendritic cell; HC, hepatocyte; IFNAR1, IFN- receptor 1; int, intermediate; NPC, nonparenchymal cell; PD-1, programmed death 1; LN, lymph node(s).