title: An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells.
abstract: Cytotoxic T lymphocyte-associated antigen-4 (CTLA-4) plays a critical role in downregulating T cell responses. A number of autoimmune diseases have shown genetic linkage to the CTLA-4 locus. We have cloned and expressed an alternatively spliced form of CTLA-4 that has genetic linkage with type I diabetes in the NOD mice. This splice variant of CTLA-4, named ligand-independent CTLA-4 (liCTLA-4), lacks exon2 including the MYPPPY motif essential for binding to the costimulatory ligands B7-1 and B7-2. Here we show that liCTLA-4 is expressed as a protein in primary T cells and strongly inhibits T cell responses by binding and dephosphorylating the TcRzeta chain. Expression of liCTLA-4, but not full-length CTLA-4 (flCTLA-4), was higher in memory/regulatory T cells from diabetes-resistant NOD congenic mice compared to susceptible NOD mice. These data suggest that increased expression and negative signaling delivered by the liCTLA-4 may regulate development of T cell-mediated autoimmune diseases.
authors.affiliation: Center for Neurologic Diseases, Department of Neurology, Boston, MA 02115 USA.
authors.forename: Lalitha
authors.initials: L
authors.lastname: Vijayakrishnan
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Slavik
authors.forename: Zsolt
authors.initials: Z
authors.lastname: Illés
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Greenwald
authors.forename: Dan
authors.initials: D
authors.lastname: Rainbow
authors.forename: Bernhard
authors.initials: B
authors.lastname: Greve
authors.forename: Laurence B
authors.initials: LB
authors.lastname: Peterson
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
authors.forename: Gordon J
authors.initials: GJ
authors.lastname: Freeman
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Linda S
authors.initials: LS
authors.lastname: Wicker
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Kuchroo
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D001327:Autoimmune Diseases; D018122:B7-1 Antigen / Q000235:genetics* / Q000276:immunology; D015153:Blotting, Western; D060908:CTLA-4 Antigen; D003001:Cloning, Molecular; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D018122:B7-1 Antigen; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D008565:Membrane Proteins; D012333:RNA, Messenger; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain