An autoimmune disease-associated CTLA-4 splice variant lacking the B7 binding domain signals negatively in T cells.
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.
Vijayakrishnan
Lalitha
L
Center for Neurologic Diseases, Department of Neurology, Boston, MA 02115 USA.
Slavik
Jacqueline M
JM
Illés
Zsolt
Z
Greenwald
Rebecca J
RJ
Rainbow
Dan
D
Greve
Bernhard
B
Peterson
Laurence B
LB
Hafler
David A
DA
Freeman
Gordon J
GJ
Sharpe
Arlene H
AH
Wicker
Linda S
LS
Kuchroo
Vijay K
VK
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*
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