An autoimmune disease-associated CTLA4 splice variant lacking the B7 binding domain signals negatively in T cells.
Cytotoxic T lymphocyte-associated antigen 4 (CTLA4) plays a critical role in down-regulating T cell responses. A number of autoimmune diseases have shown genetic linkage to the CTLA4 locus. We have cloned and expressed an alternatively spliced form of CTLA4 that has genetic linkage with type 1 diabetes in NOD mice. This splice variant of CTLA4, named ligand-independent CTLA4 (liCTLA4), lacks exon 2 including the MYPPPY motif essential for binding to the costimulatory ligands B7-1 and B7-2. liCTLA4 is expressed as a protein in primary T cells and strongly inhibits T cell responses by binding and dephosphorylating the TcRzeta chain. Expression of liCTLA4, but not full length CTLA4 (flCTLA4), was higher in memory/regulatory T cells from diabetes resistant NOD congenic mice compared to susceptible NOD mice. Transgenic expression of liCTLA4 in autoimmune prone Ctla4 -/- mice inhibited spontaneous T cell activation and prevented early lethality in the Ctla4 -/- mice. Thus, increased expression and negative signalling delivered by the liCTLA4 may play a critical role in regulating the development of T cell-mediated autoimmune diseases.
Center for Neurologic Diseases, Department of Neurology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
Lalitha
L
Vijayakrishnan
Jacqueline M
JM
Slavik
Zsolt
Z
Illés
Dan
D
Rainbow
Laurence B
LB
Peterson
Arlene S
AS
Sharpe
Linda S
LS
Wicker
Vijay K
VK
Kuchroo
D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000235:genetics*; D001327:Autoimmune Diseases / Q000235:genetics*; D001483:Base Sequence; D018106:CD28 Antigens / Q000235:genetics; D060908:CTLA-4 Antigen; D018076:DNA, Complementary; D003922:Diabetes Mellitus, Type 1 / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012326:RNA Splicing; D013601:T-Lymphocytes / Q000276:immunology*
D015703:Antigens, CD; D000943:Antigens, Differentiation; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018076:DNA, Complementary