title: Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4.
abstract: The B7-CD28/CTLA-4 costimulatory pathway can provide a signal pivotal for T cell activation. Signaling through this pathway is complex due to the presence of two B7 family members, B7-1 and B7-2, and two counterreceptors, CD28 and CTLA-4. Studies with anti-CTLA-4 monoclonal antibodies have suggested both positive and negative roles for CTLA-4 in T cell activation. To elucidate the in vivo function of CTLA-4, we generated CTLA-4-deficient mice. These mice rapidly develop lymphoproliferative disease with multiorgan lymphocytic infiltration and tissue destruction, with particularly severe myocarditis and pancreatitis, and die by 3-4 weeks of age. The phenotype of the CTLA-4-deficient mouse strain is supported by studies that have suggested a negative role for CTLA-4 in T cell activation. The severe phenotype of mice lacking CTLA-4 implies a critical role for CTLA-4 in down-regulating T cell activation and maintaining immunologic homeostasis. In the absence of CTLA-4, peripheral T cells are activated, can spontaneously proliferate, and may mediate lethal tissue injury.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: E A
authors.initials: EA
authors.lastname: Tivol
authors.forename: F
authors.initials: F
authors.lastname: Borriello
authors.forename: A N
authors.initials: AN
authors.lastname: Schweitzer
authors.forename: W P
authors.initials: WP
authors.lastname: Lynch
authors.forename: J A
authors.initials: JA
authors.lastname: Bluestone
authors.forename: A H
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D001483:Base Sequence; D060908:CTLA-4 Antigen; D002478:Cells, Cultured; D016207:Cytokines / Q000096:biosynthesis; D017931:DNA Primers / Q000737:chemistry; D015536:Down-Regulation / Q000235:genetics; D018796:Immunoconjugates; D007150:Immunohistochemistry; D008213:Lymphocyte Activation / Q000235:genetics; D008221:Lymphoid Tissue / Q000473:pathology*; D008232:Lymphoproliferative Disorders / Q000235:genetics* / Q000401:mortality / Q000473:pathology*; D051379:Mice; D008817:Mice, Mutant Strains; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D014781:Viscera / Q000473:pathology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D016207:Cytokines; D017931:DNA Primers; D018796:Immunoconjugates; D000069594:Abatacept