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Cutting Edge: B and T Lymphocyte Attenuator Signaling on NKT Cells Inhibits Cytokine Release and Tissue Injury in Early Immune Responses¹

Committee on Immunology and Department of Pathology, University of Chicago, Chicago, IL 60637

The role of coinhibition in an immune response is thought to be critical for the contraction of an adaptive immune response in its waning phases. We present evidence that B and T lymphocyte attenuator (BTLA) coinhibitory signaling is required to temper early inflammation. Using an in vivo Con A challenge model of acute hepatitis, we observed reduced survival and increased early serum cytokine secretion in BTLA^–/– mice as compared with wild-type mice. In vitro, liver mononuclear cells from BTLA^–/– mice are hyperresponsive to anti-CD3, Con A, and -galactosylceramide stimulation and secrete higher levels of TNF-, IFN-, IL-2, and IL-4. We found this was in part due to negative regulation of NKT cells by BTLA, as early cytokine inhibition from whole liver mononuclear cells or purified NKT cells depends upon BTLA signaling. Overall, our data demonstrate that coinhibition is active in early immune responses through BTLA regulation of NKT cells.

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 National Institutes of Health Grants AI062026, CA115540, and DK58891 (to Y.-X.F.).

² Address correspondence and reprint requests to Prof. Yang-Xin Fu, University of Chicago Medical Center, 5841 South Maryland Avenue, MC 3083, Chicago, IL 60637. E-mail address: yfu{at}uchicago.edu

³ Abbreviations used in this paper: BTLA, B and T lymphocyte attenuator; ALT, alanine aminotransferase; CBA, cytokine bead array; DKO, double knockout; -GalCer, -galactosylceramide; HVEM, herpes virus entry mediator; MNC, mononuclear cells.

⁴ The online version of this article contains supplemental material.