title: The B7 family revisited.
abstract: The discovery of new functions for the original B7 family members, together with the identification of additional B7 and CD28 family members, have revealed new ways in which the B7:CD28 family regulates T cell activation and tolerance. B7-1/B7-2:CD28 interactions not only promote initial T cell activation but also regulate self-tolerance by supporting CD4+CD25+ T regulatory cell homeostasis. CTLA-4 can exert its inhibitory effects in both B7-1/B7-2 dependent and independent fashions. B7-1 and B7-2 can signal bidirectionally by engaging CD28 and CTLA-4 on T cells and by delivering signals into B7-expressing cells. The five new B7 family members, ICOS ligand, PD-L1 (B7-H1), PD-L2 (B7-DC), B7-H3, and B7-H4 (B7x/B7-S1) are expressed on professional antigen-presenting cells as well as on cells within nonlymphoid organs, providing new means for regulating T cell activation and tolerance in peripheral tissues. The new CD28 families members, ICOS, PD-1, and BTLA, are inducibly expressed on T cells, and they have important roles in regulating previously activated T cells. PD-1 and BTLA also are expressed on B cells and may have broader immunoregulatory functions. The ICOS:ICOSL pathway appears to be particularly important for stimulating effector T cell responses and T cell-dependent B cell responses, but it also has an important role in regulating T cell tolerance. In addition, the PD-1:PD-L1/PD-L2 pathway plays a critical role in regulating T cell activation and tolerance. In this review, we revisit the roles of the B7:CD28 family members in regulating immune responses, and we discuss their therapeutic potential.
authors.affiliation: Department of Pathology, Harvard Medical School and Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. rgreenwald@rics.bwh.harvard.edu
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Greenwald
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D000943:Antigens, Differentiation / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D001249:Asthma / Q000209:etiology / Q000628:therapy; D015551:Autoimmunity; D018122:B7-1 Antigen / Q000276:immunology*; D051940:B7-2 Antigen; D018106:CD28 Antigens / Q000276:immunology; D060908:CTLA-4 Antigen; D006801:Humans; D006967:Hypersensitivity / Q000209:etiology / Q000628:therapy; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007239:Infections / Q000209:etiology / Q000628:therapy; D008562:Membrane Glycoproteins / Q000276:immunology; D051379:Mice; D011506:Proteins / Q000276:immunology; D014181:Transplantation Immunology
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D000945:Antigens, Differentiation, T-Lymphocyte; D018122:B7-1 Antigen; D051940:B7-2 Antigen; D018106:CD28 Antigens; C497964:CD86 protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C497965:Cd86 protein, mouse; C556707:Ctla4 protein, mouse; C556692:ICOS protein, human; C498514:ICOSLG protein, human; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D008562:Membrane Glycoproteins; D011506:Proteins