The Journal of Experimental Medicine
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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 an antitumor immune response. To better understand the antitumor effects of anti-cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) antibody treatment, we analyzed the effect of CTLA-4 signaling on CD8+ T cells in vitro and in vivo. In vitro, cross-linking of CTLA-4 on purified CD8+ T cells caused decreased proliferative responses to anti-CD3 stimulation and rapid loss of activation marker expression. In vivo, blockade of CTLA-4 by neutralizing anti–CTLA-4 mAb greatly enhanced the accumulation, activation, and cytotoxic activity of CD8+ T cells induced by immunization with Ag on dendritic cells (DC). This enhanced response did not require the expression of MHC class II molecules on DC or the presence of CD4+ T cells. These results demonstrate that CTLA-4 blockade is able to directly enhance the proliferation and activation of specific CD8+ T cells, indicating its potential for tumor immunotherapy even in situations in which CD4+ T cell 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 Institute of 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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