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B and T Lymphocyte Attenuator Tempers Early Infection Immunity¹

Yonglian Sun^2,3,*, Nicholas K. Brown^2,*, Matthew J. Ruddy^*, Mendy L. Miller^*, Youjin Lee^*, Yang Wang^*, Kenneth M. Murphy, Klaus Pfeffer, Lieping Chen, Jonathan Kaye^¶ and Yang-Xin Fu^4,*

^* Department of Pathology, University of Chicago, Chicago, IL 60637; Department of Pathology and Center for Immunology, Washington University, St. Louis, MO 63110; Institute of Medical Microbiology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; Department of Dermatology, Johns Hopkins University, Baltimore, MD 21205; and ^¶ Department of Immunology, the Scripps Research Institute, La Jolla, CA 92037

Coinhibitory pathways are thought to act in later stages of an adaptive immune response, but whether coinhibition contributes to early innate immunity is unclear. We show that engagement of the newly discovered coinhibitory receptor B and T lymphocyte attenuator (BTLA) by herpesvirus entry mediator (HVEM) is critical for negatively regulating early host immunity against intracellular bacteria. Both HVEM^–/– and BTLA^–/–, but not LIGHT^–/–, mice are more resistant to listeriosis compared with wild-type mice, and blockade of the BTLA pathway promotes, while engagement inhibits, early bacterial clearance. Differences in bacterial clearance were seen as early as 1 day postinfection, implicating the initial innate response. Therefore, innate cell function in BTLA^–/– mice was studied. We show that innate cells from BTLA^–/– mice secrete significantly more proinflammatory cytokines upon stimulation with heat-killed Listeria. These results provide the first evidence that a coinhibitory pathway plays a critical role in regulating early host innate immunity against infection.

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 These studies were supported in part by National Institutes of Health Grants CA115540, AI062026, and DK58897 to Y.-X.F. N.K.B. was supported by National Institutes of Health Training Grant T32AI007090.

² Y.S. and N.K.B. contributed equally to this paper.

³ Current address: Genentech, 1 DNA Way/MS 34, South San Francisco, CA 94080.

⁴ Address correspondence and reprint requests to Dr. Yang-Xin Fu, Department of Pathology, The University of Chicago, 5841 South Maryland, S354, MC3083, Chicago, IL 60637. E-mail address: yxfu{at}bsd.uchicago.edu

⁵ Abbreviations used in this paper: BTLA, B and T lymphocyte attenuator; DC, dendritic cell; HKLM, heat-killed Listeria monocytogenes; HVEM, herpesvirus entry mediator; LM, Listeria monocytogenes; WT, wild type.