Ligation of B and T lymphocyte attenuator prevents the genesis of experimental cerebral malaria.
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.
Lepenies
Bernd
B
Department of Immunology, Bernhard Nocht Institute for Tropical Medicine, Hamburg, Germany.
Pfeffer
Klaus
K
Hurchla
Michelle A
MA
Murphy
Theresa L
TL
Murphy
Kenneth M
KM
Oetzel
Juliane
J
Fleischer
Bernhard
B
Jacobs
Thomas
T
D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D000913:Antibodies, Protozoan / Q000008:administration & dosage; D001921:Brain / Q000098:blood supply / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D005260:Female; D008024:Ligands; D008213:Lymphocyte Activation / Q000276:immunology; D016779:Malaria, Cerebral / Q000276:immunology* / Q000469:parasitology / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008833:Microcirculation / Q000276:immunology / Q000469:parasitology / Q000473:pathology; D010962:Plasmodium berghei / Q000254:growth & development / Q000276:immunology; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism* / Q000502:physiology; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology / Q000469:parasitology / Q000473:pathology