Molecular Basis of T Cell Inactivation by CTLA-4

• DOI: 10.1126/science.282.5397.2263
• Publication Date: 2002-07-27T09:37:56Z
• Authors: Kyung-Mi Lee; Ellen Chuang; Matthew Griffin; Roli Khattri; David K. Hong; Weiguo Zhang; David Straus; Lawrence E. Samelson; Craig B. Thompson; Jeffrey A. Bluestone
• Keywords: 0301 basic medicine; Mice, Inbred BALB C; Immunoconjugates; Protein Tyrosine Phosphatase, Non-Receptor Type 6; Intracellular Signaling Peptides and Proteins; Models, Immunological; Membrane Proteins; Protein Tyrosine Phosphatase, Non-Receptor Type 11; Lymphocyte Activation; Antigens, Differentiation; Cell Line; Abatacept; Mice; 03 medical and health sciences; 0302 clinical medicine; Antigens, CD; Lymphocyte Specific Protein Tyrosine Kinase p56(lck); Animals; Humans; CTLA-4 Antigen; Phosphorylation; Phosphotyrosine; Cells, Cultured

CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex ζ chain in primary T cells. The association of TCRζ with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56 lck -induced tyrosine phosphorylation. Coexpression of the CTLA-4–associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRζ bound to CTLA-4 and abolished the p56 lck -inducible TCRζ–CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRζ and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance.