Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152)

Matthew D. Griffin, David K. Hong, Philmore O. Holman, Kyung Mi Lee, Matthew J. Whitters, Sean M. O'Herrin, Francesca Fallarino, Mary Collins, David M. Segal, Thomas F. Gajewski, David M. Kranz, Jeffrey A. Bluestone

Research output: Contribution to journalArticle

Abstract

CTLA-4 (CD152) engagement can down-regulate T cell activation and promote the induction of immune tolerance. However, the strategy of attenuating T cell activation by engaging CTLA-4 has been limited by sharing of its natural ligands with the costimulatory protein CD28. In the present study, a CTLA-4-specific single-chain Ab (scFv) was developed and expressed on the cell surface to promote selective engagement of this regulatory molecule. Transfectants expressing anti-CTLA-4 scfv at their surface bound soluble CTLA-4 but not soluble CD28. Coexpression of anti-CTLA-4 scfv with anti-CD3ε anti-CD28 scFvs on artificial APCs reduced the proliferation and IL.2 production by resting and preactivated bulk T cells as well as CD4+ and CD8+ T cell subsets. Importantly, expression of anti-CTLA-4 ssFv on the same cell surface as the TCR ligand was essential for the inhibitory effects of CTLA-4-specific ligation. CTLA-4-mediated inhibition of tyrosine phosphorylation of components of the proximal TCR signaling apparatus was similarly dependent on coexpression of TCR and CTLA-4 ligands on the same surface. These findings support a predominant role for CTLA-4 function in the modification of the proximal TCR signal. Using T cells from DO11.10 and 2C TCR transgenic mice, negative regulatory effects of selective CTLA-4 ligation were also demonstrated during the stimulation of Ag-specific CD4+ anti CD8+ T cells by MHC/peptide complexes. Together these studies demonstrate that selective ligation of CTLA-4 using a membrane-bound scfv results in attenuated T cell responses only when coengaged with the TCR during T cell/APC interaction and define an approach to harnessing the immunomodulatory potential of CTLA-4-specific ligation.

Original languageEnglish (US)
Pages (from-to)4433-4442
Number of pages10
JournalJournal of Immunology
Volume164
Issue number9
DOIs
StatePublished - May 1 2000

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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  • Cite this

    Griffin, M. D., Hong, D. K., Holman, P. O., Lee, K. M., Whitters, M. J., O'Herrin, S. M., Fallarino, F., Collins, M., Segal, D. M., Gajewski, T. F., Kranz, D. M., & Bluestone, J. A. (2000). Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152). Journal of Immunology, 164(9), 4433-4442. https://doi.org/10.4049/jimmunol.164.9.4433