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 dia...

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Bibliographic Details
Published in:Immunity (Cambridge, Mass.) Mass.), 2004-05, Vol.20 (5), p.563-575
Main Authors: Vijayakrishnan, Lalitha, Slavik, Jacqueline M, Illés, Zsolt, Greenwald, Rebecca J, Rainbow, Dan, Greve, Bernhard, Peterson, Laurence B, Hafler, David A, Freeman, Gordon J, Sharpe, Arlene H, Wicker, Linda S, Kuchroo, Vijay K
Format: Article
Language:English
Subjects:
Amino Acid Sequence
Animals
Antigens, CD
Antigens, Differentiation - biosynthesis
Antigens, Differentiation - genetics
Antigens, Differentiation - immunology
Autoimmune Diseases
B7-1 Antigen - genetics
B7-1 Antigen - immunology
Blotting, Western
Cloning
Cloning, Molecular
CTLA-4 Antigen
Diabetes
Disease
Female
Flow Cytometry
Gene expression
Humans
Ligands
Lymphocytes
Membrane Proteins - metabolism
Mice
Mice, Inbred NOD
Molecular Sequence Data
Phosphorylation
Proteins
Receptors, Antigen, T-Cell - metabolism
Reverse Transcriptase Polymerase Chain Reaction
RNA, Messenger - analysis
Signal Transduction - immunology
T-Lymphocytes - immunology
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Summary: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.
ISSN:1074-7613
1097-4180
DOI:10.1016/S1074-7613(04)00110-4