Molecular Basis of T Cell Inactivation by CTLA-4

TLDR

CTLA‑4, a negative regulator of T cell function, associates with the TCR ζ chain in primary T cells. CTLA‑4 binds TCRζ, and its interaction is promoted by p56 lck‑induced phosphorylation but is disrupted by SHP‑2‑mediated dephosphorylation, thereby inhibiting TCR signal transduction and highlighting its role in negative regulation of T cell function and tolerance.

Abstract

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.