B and T lymphocyte attenuator tempers early infection immunity.
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.
Sun
Yonglian
Y
Department of Pathology, University of Chicago, Chicago, IL 60637, USA.
Brown
Nicholas K
NK
Ruddy
Matthew J
MJ
Miller
Mendy L
ML
Lee
Youjin
Y
Wang
Yang
Y
Murphy
Kenneth M
KM
Pfeffer
Klaus
K
Chen
Lieping
L
Kaye
Jonathan
J
Fu
Yang-Xin
YX
D000818:Animals; D001424:Bacterial Infections / Q000276:immunology*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D007113:Immunity, Innate / Q000276:immunology*; D008087:Listeria / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding / Q000276:immunology; D011971:Receptors, Immunologic / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D053240:Receptors, Tumor Necrosis Factor, Member 14 / Q000172:deficiency / Q000276:immunology* / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology
C488868:BTLA protein, mouse; D016207:Cytokines; D011971:Receptors, Immunologic; D053240:Receptors, Tumor Necrosis Factor, Member 14