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The Journal of Immunology, Vol 156, Issue 3 1047-1054, Copyright © 1996 by American Association of Immunologists

ARTICLES

Differential effects of CTLA-4 substitutions on the binding of human CD80 (B7-1) and CD86 (B7-2)

PA Morton, XT Fu, JA Stewart, KS Giacoletto, SL White, CE Leysath, RJ Evans, JJ Shieh and RW Karr
Department of Immunology, G. D. Searle & Company, St. Louis, MO 63198, USA.

CTLA-4 expressed on activated T cells binds to CD80 (B7-1) and CD86 (B7- 2) molecules present on APC with high avidity and appears to deliver a negative regulatory signal to the T cell. We have investigated the kinetics of CTLA-4 binding to CD80 and CD86, together with the effects of selected CTLA-4 mutations on binding activity. The dissociation constants (Kd) for binding of CTLA-4-Ig to CD80 and CD86 transfectants were 8.1 and 6.7 nM, respectively. Surface plasmon resonance was used to determine kinetic parameters of CTLA-4-Ig binding to CD80-Ig and CD86-Ig fusion proteins and revealed enhanced association (ka) and dissociation (kd) rate constants for CD86-Ig compared with CD80-Ig. Furthermore, CD80-Ig and CD86-Ig fusion molecules demonstrated variable abilities to cross-compete for binding to several modified forms of CTLA-4-Ig. Differential binding of CD80 and CD86 to CTLA-4 was further revealed by analysis of 10 discrete CTLA-4 mutants. Five single amino acid substitutions within the CTLA-4 MYPPPY domain exerted modest effects on CD80 binding, but each of these substitutions completely abrogated CD86 binding. In addition, substitutions just N-terminal of the MYPPPY region, and within the CDR1-like region of CTLA-4, eliminated both CD80 and CD86 binding. Hence, CD80 and CD86 bind with different association/dissociation kinetics to similar, but distinct, sites on CTLA-4.


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