Cutting edge: B and T lymphocyte attenuator signaling on NKT cells inhibits cytokine release and tissue injury in early immune responses.
The role of coinhibition in an immune response is thought to be critical for the contraction of an adaptive immune response in its waning phases. We present evidence that B and T lymphocyte attenuator (BTLA) coinhibitory signaling is required to temper early inflammation. Using an in vivo Con A challenge model of acute hepatitis, we observed reduced survival and increased early serum cytokine secretion in BTLA(-/-) mice as compared with wild-type mice. In vitro, liver mononuclear cells from BTLA(-/-) mice are hyperresponsive to anti-CD3, Con A, and alpha-galactosylceramide stimulation and secrete higher levels of TNF-alpha, IFN-gamma, IL-2, and IL-4. We found this was in part due to negative regulation of NKT cells by BTLA, as early cytokine inhibition from whole liver mononuclear cells or purified NKT cells depends upon BTLA signaling. Overall, our data demonstrate that coinhibition is active in early immune responses through BTLA regulation of NKT cells.
Miller
Mendy L
ML
Committee on Immunology and Department of Pathology, University of Chicago, IL 60637, USA.
Sun
Yonglian
Y
Fu
Yang-Xin
YX
D000208:Acute Disease; D000818:Animals; D056486:Chemical and Drug Induced Liver Injury / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D002999:Clone Cells; D003208:Concanavalin A / Q000008:administration & dosage; D016207:Cytokines / Q000037:antagonists & inhibitors* / Q000378:metabolism* / Q000502:physiology; D005260:Female; D018836:Inflammation Mediators / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology; D008099:Liver / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D055611:Natural Killer T-Cells / Q000276:immunology* / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000502:physiology*; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology*; D013997:Time Factors
C488868:BTLA protein, mouse; D016207:Cytokines; D018836:Inflammation Mediators; D011971:Receptors, Immunologic; D003208:Concanavalin A