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* Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, La Jolla, CA 92037;
Department of Pathology, University of Chicago, Chicago, IL 60637;
Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110; and
Institute of Medical Microbiology, University of Düsseldorf, Düsseldorf, Germany
Proliferation of dendritic cells (DC) in the spleen is regulated by positive growth signals through the lymphotoxin (LT)-β receptor; however, the countering inhibitory signals that achieve homeostatic control are unresolved. Mice deficient in LT
, LTβ, LTβR, and the NF
B inducing kinase show a specific loss of CD8– DC subsets. In contrast, the CD8– DC subsets were overpopulated in mice deficient in the herpesvirus entry mediator (HVEM) or B and T lymphocyte attenuator (BTLA). HVEM- and BTLA-deficient DC subsets displayed a specific growth advantage in repopulating the spleen in competitive replacement bone marrow chimeric mice. Expression of HVEM and BTLA were required in DC and in the surrounding microenvironment, although DC expression of LTβR was necessary to maintain homeostasis. Moreover, enforced activation of the LTβR with an agonist Ab drove expansion of CD8– DC subsets, overriding regulation by the HVEM-BTLA pathway. These results indicate the HVEM-BTLA pathway provides an inhibitory checkpoint for DC homeostasis in lymphoid tissue. Together, the LTβR and HVEM-BTLA pathways form an integrated signaling network regulating DC homeostasis.
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 supported in part by grants from the Public Health Service, National Institutes of Health, AI33068, CA69381, AI48073, and AI06789.
2 Address correspondence and reprint requests to Dr. Carl F. Ware, Division of Molecular Immunology, La Jolla Institute for Allergy and Immunology, 9420 Athena Circle, La Jolla, CA 92037. E-mail address: cware{at}liai.org
3 Abbreviations used in this paper: BTLA, B and T lymphocyte attenuator; HVEM, herpesvirus entry mediator; ICSBP, IFN consensus sequence binding factor; IRF, IFN response factor; LIGHT, LT-related inducible ligand that competes for glycoprotein D binding to HVEM on T cells; LT, lymphotoxin; NIK, NFB-inducing kinase; pDC plasmacytoid DC; wt, wild type.
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