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TCR subunit specificity of CTLA‐4‐mediated signaling
Author(s) -
Siu Eric,
Carreno Beatriz M.,
Madrenas Joaquín
Publication year - 2003
Publication title -
journal of leukocyte biology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.819
H-Index - 191
eISSN - 1938-3673
pISSN - 0741-5400
DOI - 10.1189/jlb.0503198
Subject(s) - il 2 receptor , biology , t cell receptor , t cell , cytotoxic t cell , microbiology and biotechnology , cd3 , jurkat cells , signal transduction , antigen , cd8 , immune system , immunology , biochemistry , in vitro
Cytotoxic T‐lymphocyte‐associated antigen (CTLA)‐4 is an activation‐induced receptor that down‐regulates T cell responses by antagonizing B7‐dependent costimulation and/or by transducing a negative signal. The mechanism of CTLA‐4‐mediated negative signaling is unknown. Recently, it has been postulated that CTLA‐4 inhibits T cell activation by causing specific dephosphorylation of the T cell receptor (TCR)‐ζ chain of the antigen‐receptor complex through an lck‐dependent recruitment of the Src homology‐2‐containing tyrosine phosphatase‐2. To test this hypothesis, we generated stably transfected T cell clones expressing doxycycline‐inducible CTLA‐4 with CD25:TCR‐ζ (CD25‐ζ) or CD25:CD3‐ɛ (CD25‐ɛ) fusion proteins. In these clones, ligation of CD25‐ζ or of CD25‐ɛ with antibodies against CD25 induced full T cell activation, as illustrated by extracellular signal‐regulated kinase (ERK) activation and interleukin (IL)‐2 production. More importantly, coligation of CTLA‐4 with CD25‐ζ or of CTLA‐4 with CD25‐ɛ in the respectively transfected clones inhibited ERK activation and IL‐2 production, demonstrating that CTLA‐4 does not specifically inhibit signals from TCR‐ζ but can also inhibit signals from CD3‐ɛ. Our results suggest that the target specificity of CTLA‐4 is determined by its coligation with any given transmembrane receptor rather than by its intracellular mediators.