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* Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany;
Institute of Medical Microbiology, Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany; and
Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110
B and T lymphocyte attenuator (BTLA; CD272) is a coinhibitory receptor that is predominantly expressed on T and B cells and dampens T cell activation. In this study, we analyzed the function of BTLA during infection with Plasmodium berghei ANKA. Infection of C57BL/6 mice with this strain leads to sequestration of leukocytes in brain capillaries that is associated with a pathology resembling cerebral malaria in humans. During the course of infection, we found an induction of BTLA in several organs, which was either due to up-regulation of BTLA expression on T cells in the spleen or due to infiltration of BTLA-expressing T cells into the brain. In the brain, we observed a marked induction of BTLA and its ligand herpesvirus entry mediator during cerebral malaria, which was accompanied by an accumulation of predominantly CD8+ T cells, but also CD4+ T cells. Application of an agonistic anti-BTLA mAb caused a significantly reduced incidence of cerebral malaria compared with control mice. Treatment with this Ab also led to a decreased number of T cells that were sequestered in the brain of P. berghei ANKA-infected mice. Our findings indicate that BTLA-herpesvirus entry mediator interactions are functionally involved in T cell regulation during P. berghei ANKA infection of mice and that BTLA is a potential target for therapeutic interventions in severe malaria.
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 Grant JA 1451 (to T. J.).
2 Address correspondence and reprint requests to Dr. Thomas Jacobs, Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht-Strasse 74, Hamburg, Germany. E-mail address: tjacobs{at}bni-hamburg.de
3 Abbreviations used in this paper: CM, cerebral malaria; PbA, Plasmodium berghei ANKA; BTLA, B and T lymphocyte attenuator; HVEM, herpesvirus entry mediator; p.i., postinfection; Treg, regulatory T cell; GVHD, graft-versus-host.
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