The Journal of Immunology B and T Lymphocyte Attenuator Restricts the Protective Immune Response against Experimental Malaria Guido Adler,* Christiane Steeg,* Klaus Pfeffer, † Theresa L. Murphy, ‡ Kenneth M. Murphy, ‡ Jean Langhorne, x and Thomas Jacobs* The immune response against the blood stage of malaria has to be tightly regulated to allow for vigorous antiplasmodial activity while restraining potentially lethal immunopathologic damage to the host like cerebral malaria. Coinhibitory cell surface receptors are important modulators of immune activation. B and T lymphocyte attenuator (BTLA) (CD272) is a coinhibitory receptor expressed by most leukocytes, with the highest expression levels on T and B cells, and is involved in the maintenance of peripheral tolerance by dampening the activation of lymphocytes. The function of BTLA is described in several models of inflammatory dis- orders and autoimmunity, but its function in infectious diseases is less well characterized. Also, little is known about the influence of BTLA on non-T cells. In this study, we analyzed the function of BTLA during blood-stage malaria infection with the nonlethal Plasmodium yoelii strain 17NL. We show that BTLA knockout mice exhibit strongly reduced parasitemia and clear the infection earlier compared with wild-type mice. This increased resistance was seen before the onset of adaptive immune mechanisms and even in the absence of T and B cells but was more pronounced at later time points when activation of T and B cells was observed. We demonstrate that BTLA regulates production of proinflammatory cytokines in a T cell-intrinsic way and B cell intrinsically regulates the production of P. yoelii 17NL-specific Abs. These results indicate that the coinhibitory receptor BTLA plays a critical role during experimental malaria and attenuates the innate as well as the subsequent adaptive immune response. The Journal of Immunology , 2011, 187: 5310–5319. B and T lymphocyte attenuator (BTLA) is a recently dis- covered inhibitory receptor that shares structural and functional similarities with CTLA-4 and programmed death 1 (1). Recently, the interaction partner of BTLA, named herpesvirus entry mediator (HVEM), which is a member of the TNF receptor superfamily, has been identified (2). HVEM is expressed by most cells of hematopoietic origin but also by epi- thelial and endothelial cells (3–6). HVEM also binds to the re- ceptor “homologous to lymphotoxins, inducible expression, com- petes with HSV glycoprotein D for HVEM, a receptor expressed on T lymphocytes” (LIGHT), leading to a costimulatory signal, and to CD160, which provides a coinhibitory signal (7). There- fore, HVEM can act as a molecular switch, because of its ability to provide both coinhibitory and costimulatory signals (8). BTLA is expressed constitutively by naive CD4 + and CD8 + T cells and is upregulated further upon T cell activation. It is also present on B cells and dendritic cells. In C57BL/6 mice, macrophages and monocytes also express BTLA, which reflects the situation in humans where CD14 + cells constitutively express BTLA as well (9). NK cells do not express BTLA in appreciable levels in either C57BL/6 mice or humans (1, 9, 10). This expression pattern suggests that BTLA can deliver negative signals during innate and adaptive immunity. Cross-linking of BTLA leads to tyrosine phosphorylation and recruitment of Src homology domain 2- containing protein tyrosine phosphatase 1 and 2 via immunore- ceptor tyrosine-based inhibitory/switch motifs of BTLA. In ac- cordance with the role of BTLA as a negative receptor, BTLA knockout (KO) T cells are hyperresponsive to Ag-specific acti- vation (1). In acute allergic airway inflammation, BTLA contrib- utes to the termination of the Th2-mediated immune response, because mice lacking these receptors show prolonged lung in- flammation (11). Moreover, an inhibitory function of BTLA has been demonstrated in in vivo transplantation models using MHC- mismatched cardiac allografts (12). BTLA-KO mice are also more susceptible to experimental autoimmune encephalomyelitis (1) and Con A-induced hepatitis (13). Triggering BTLA or deleting BTLA highly positive T cells also might have therapeutic sig- nificance. In a model of cerebral malaria, we have shown that an agonistic Ab can prevent experimental cerebral malaria (14) and others have shown that anti-BTLA can induce delayed onset of diabetes (15), decreased T cell-induced colitis (6), and prolonged allograft survival (15, 16). Plasmodium falciparum malaria remains one of the leading causes of morbidity and mortality, especially in sub-Saharan Africa (17). The infection starts when infected mosquitoes in- oculate sporozoites into the host during a blood meal. A few sporozoites enter the blood stream and reach the liver where they infect hepatocytes. In the liver, in particular, CD8 + T cells that recognize antigenic peptides on MHC class I can mediate pro- tection (18). However, an effective immune response is hampered by several circumstances: 1) only very little antigenic material is delivered, 2) only very few cells in the liver are infected, 3) the liver stage is very short, and 4) the liver is a tolerogenic organ. *Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany; † Institute of Medical Microbiology, Heinrich Heine University, 40225 Du ¨sseldorf, Germany; ‡ Department of Pathology and Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110; and x Division of Parasitology, Medical Research Council National Institute for Medical Research, London NW7 1AA, United Kingdom Received for publication May 17, 2011. Accepted for publication September 2, 2011. This work was supported by Collaborative Research Center 841 of the Deutsche Forschungsgemeinschaft. Address correspondence and reprint requests to Dr. Thomas Jacobs, Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Bernhard-Nocht- Strasse 74, 20359 Hamburg, Germany. E-mail address: tjacobs@bni-hamburg.de Abbreviations used in this article: BTLA, B and T lymphocyte attenuator; HVEM, herpesvirus entry mediator; KO, knockout; LIGHT, homologous to lymphotoxins, inducible expression, competes with herpes simplex virus glycoprotein D for HVEM, a receptor expressed on T lymphocytes; PyNL, Plasmodium yoelii strain 17NL. Copyright Ó 2011 by The American Association of Immunologists, Inc. 0022-1767/11/$16.00 www.jimmunol.org/cgi/doi/10.4049/jimmunol.1101456