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

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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
Pages (from-to)4433-4442
Number of pages10
JournalJournal of Immunology
Volume164
Issue number9
Publication statusPublished - 2000 May 1
Externally publishedYes

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Single-Chain Antibodies
T-Lymphocytes
Ligation
Ligands
Immune Tolerance
T-Lymphocyte Subsets
Cell Communication
Transgenic Mice
Tyrosine
Down-Regulation
Phosphorylation
Peptides
Membranes

ASJC Scopus subject areas

  • Immunology

Cite this

Griffin, M. D., Hong, D. K., Holman, P. O., Lee, K-M., Whitters, M. J., O'Herrin, S. 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.

Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152). / Griffin, Matthew D.; Hong, David K.; Holman, Philmore O.; Lee, Kyung-Mi; Whitters, Matthew J.; O'Herrin, Sean M.; Fallarino, Francesca; Collins, Mary; Segal, David M.; Gajewski, Thomas F.; Kranz, David M.; Bluestone, Jeffrey A.

In: Journal of Immunology, Vol. 164, No. 9, 01.05.2000, p. 4433-4442.

Research output: Contribution to journalArticle

Griffin, MD, Hong, DK, Holman, PO, Lee, K-M, Whitters, MJ, O'Herrin, SM, Fallarino, F, Collins, M, Segal, DM, Gajewski, TF, Kranz, DM & Bluestone, JA 2000, 'Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152)', Journal of Immunology, vol. 164, no. 9, pp. 4433-4442.
Griffin MD, Hong DK, Holman PO, Lee K-M, Whitters MJ, O'Herrin SM et al. Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152). Journal of Immunology. 2000 May 1;164(9):4433-4442.
Griffin, Matthew D. ; Hong, David K. ; Holman, Philmore O. ; Lee, Kyung-Mi ; Whitters, Matthew J. ; O'Herrin, Sean M. ; Fallarino, Francesca ; Collins, Mary ; Segal, David M. ; Gajewski, Thomas F. ; Kranz, David M. ; Bluestone, Jeffrey A. / Blockade of T cell activation using a surface-linked single-chain antibody to CTLA-4 (CD152). In: Journal of Immunology. 2000 ; Vol. 164, No. 9. pp. 4433-4442.
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