Cytotoxic T Lymphocyte-associated Antigen 4 (CTLA-4) Can Regulate Dendritic Cell-induced Activation and Cytotoxicity of CD8+ T Cells Independently of CD4+T Cell Help

doi:10.1084/jem.189.7.1157

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© The Rockefeller University Press, 0022-1007/1999/4/1157/ $5.00
The Journal of Experimental Medicine, Volume 189, Number 7, April 5, 1999 1157-1162

Brief Definitive Reports

Cytotoxic T Lymphocyte–associated Antigen 4 (CTLA-4) Can Regulate Dendritic Cell–induced Activation and Cytotoxicity of CD8⁺ T Cells Independently of CD4⁺T Cell Help

Kathy D. McCoy, Ian F. Hermans, J. Henry Fraser, Graham Le Gros, and Franca Ronchese

From the Malaghan Institute of Medical Research, Wellington School of Medicine, Wellington, New Zealand

The mechanisms that regulate the strength and duration of CD8⁺cytotoxic T cell activity determine the effectiveness of anantitumor immune response. To better understand the antitumoreffects of anti-cytotoxic T lymphocyte–associated antigen4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4signaling on CD8⁺ T cells in vitro and in vivo. In vitro, cross-linkingof CTLA-4 on purified CD8⁺ T cells caused decreased proliferativeresponses to anti-CD3 stimulation and rapid loss of activationmarker expression. In vivo, blockade of CTLA-4 by neutralizinganti–CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8⁺ T cells induced by immunizationwith Ag on dendritic cells (DC). This enhanced response didnot require the expression of MHC class II molecules on DCor the presence of CD4⁺ T cells. These results demonstrate thatCTLA-4 blockade is able to directly enhance the proliferationand activation of specific CD8⁺ T cells, indicating its potential for tumor immunotherapy even in situations in which CD4⁺ Tcell help is limited or absent.

Key Words: CTLA-4 (CD152) • CD8⁺ T cells • dendritic cells • CD4⁺ T cells • cytotoxicity

Address correspondence to Franca Ronchese, Malaghan Instituteof Medical Research, P.O. Box 7060, Wellington South, New Zealand;Phone: 64-4-389-5096; Fax: 64-4-389-5095; E-mail: mimrfr{at}wnmeds.ac.nz

K. McCoy's present address is Institute for Experimental Immunology,University of Zürich, Schmelzbergstrasse 12, CH-8091 Zürich,Switzerland.

K.D. McCoy and I.F. Hermans contributed equally to this study.

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