title: Differential effects of B and T lymphocyte attenuator and programmed death-1 on acceptance of partially versus fully MHC-mismatched cardiac allografts.
abstract: Although fully MHC-mismatched murine cardiac allografts are rapidly rejected, allografts mismatched at only MHC class I or class II alleles survive long term; the immunologic basis for the long-term survival of MHC class I- or II-mismatched allografts is unknown. We examined the roles of two recently described inhibitory receptors, B and T lymphocyte attenuator (BTLA) and programmed death-1 (PD-1), in the survival of partially or fully MHC-mismatched allografts using gene-deficient recipients as well as through use of blocking mAbs in wild-type hosts. Partially MHC-mismatched allografts showed strong induction of BTLA, but not PD-1 mRNA and survived long term in wild-type recipients, whereas targeting of BTLA or its ligand, herpesvirus entry mediator, but not PD-1, prompted their rapid rejection. By contrast, fully MHC-mismatched cardiac allografts were acutely rejected in wild-type recipients despite the induction of both BTLA and PD-1. Targeting of PD-1 in several fully MHC-mismatched models accelerated rejection, whereas targeting of BTLA unexpectedly enhanced PD-1 induction by alloreactive CD4 and CD8 T cells and prolonged allograft survival. In vitro studies using allogeneic dendritic cells and T cells showed that at low levels of T cell activation, BTLA expression was primarily induced, but that with increasing degrees of T cell activation, the expression of PD-1 was strongly up-regulated. These data suggest that BTLA and PD-1 exert distinct inhibitory actions in vivo, with the BTLA/herpesvirus entry mediator pathway appearing to dominate in regulating responses against a restricted degree of allogeneic mismatch.
authors.affiliation: Division of Transplantation Immunology, Department of Pathology and Laboratory Medicine, Biesecker Pediatric Liver Center, Children's Hospital of Philadelphia, PA 19104, USA.
authors.forename: Ran
authors.initials: R
authors.lastname: Tao
authors.forename: Liqing
authors.initials: L
authors.lastname: Wang
authors.forename: Rongxiang
authors.initials: R
authors.lastname: Han
authors.forename: Tao
authors.initials: T
authors.lastname: Wang
authors.forename: Qunrui
authors.initials: Q
authors.lastname: Ye
authors.forename: Takasu
authors.initials: T
authors.lastname: Honjo
authors.forename: Theresa L
authors.initials: TL
authors.lastname: Murphy
authors.forename: Kenneth M
authors.initials: KM
authors.lastname: Murphy
authors.forename: Wayne W
authors.initials: WW
authors.lastname: Hancock
mesh_terms: D000818:Animals; D000954:Antigens, Surface / Q000502:physiology*; D051017:Apoptosis Regulatory Proteins / Q000502:physiology*; D016027:Heart Transplantation / Q000276:immunology*; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006650:Histocompatibility Testing; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic / Q000502:physiology*; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000954:Antigens, Surface; D051017:Apoptosis Regulatory Proteins; C488868:BTLA protein, mouse; D000949:Histocompatibility Antigens Class II; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D018124:Receptors, Tumor Necrosis Factor; D053240:Receptors, Tumor Necrosis Factor, Member 14; D011991:Receptors, Virus; C506029:Tnfrsf14 protein, mouse