Open AccessInduction of autoimmune disease in CTLA-4−/−mice depends on a specific CD28 motif that is required forin vivocostimulation
Author(s) -
Xuguang Tai,
François Van Laethem,
Arlene H. Sharpe,
Alfred Singer
Publication year - 2007
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0706509104
Subject(s) - cd28 , biology , tyrosine kinase , in vivo , tyrosine , ex vivo , microbiology and biotechnology , autoimmunity , signal transduction , biochemistry , antigen , immunology , cd8 , antibody , genetics
CTLA-4-deficient mice develop a lethal autoimmune lymphoproliferative disorder that is strictly dependent onin vivo CD28 costimulation. Nevertheless, it is not known whether there is a specific site on the CD28 molecule that is required for induction of autoimmunity. Using CTLA-4-deficient mice expressing CD28 molecules with various point mutations in the CD28 cytosolic tail, the present study documents thatin vivo costimulation for induction of autoimmune disease strictly requires an intact C-terminal proline motif that promotes lymphocyte-specific protein tyrosine kinase Lck binding to the CD28 cytosolic tail, because point mutations in C-terminal proline residues (Pro-187 and Pro-190) completely prevented disease induction. In contrast,in vivo costimulation for disease induction did not require either an intact YMNM motif or an intact N-terminal proline motif, which, respectively, promote phosphoinositide 3-kinase and IL2-inducible T cell kinase binding to the CD28 cytosolic tail. Thus,in vivo CD28 costimulation for induction of autoimmune disease is strictly and specifically dependent on an intact C-terminal proline motif that serves as a lymphocyte-specific protein tyrosine Lck kinase binding site in the CD28 cytosolic tail.