Volume 28, Issue 4 pp. 1322-1331
Article
Free Access

LFA-3 co-stimulates cytokine secretion by cytotoxic T lymphocytes by providing a TCR-independent activation signal

Soizic Le Guiner

Soizic Le Guiner

INSERM U463 and Faculty of Sciences of Nantes, Nantes, France

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Eric Le Dréan

Eric Le Dréan

INSERM U463 and Faculty of Sciences of Nantes, Nantes, France

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Nathalie Labarrière

Nathalie Labarrière

INSERM U463 and Faculty of Sciences of Nantes, Nantes, France

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Jean-François Fonteneau

Jean-François Fonteneau

INSERM U463 and Faculty of Sciences of Nantes, Nantes, France

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Christophe Viret

Christophe Viret

Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, USA

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Elisabeth Diez

Elisabeth Diez

INSERM U463 and Faculty of Sciences of Nantes, Nantes, France

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Francine Jotereau

Francine Jotereau

INSERM U463 and Faculty of Sciences of Nantes, Nantes, France

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Abstract

T cell activation is known to depend not only on efficient antigen recognition and subsequent signaling through TCR, but also on interactions involving multiple adhesion and accessory molecules such as CD28/B7, LFA-1/ICAM-1 and LFA-3/CD2. The present study dissects the role of LFA-3/CD2 interactions in the activation of melanoma-specific CD8+ T cell clones. To this end we analyzed the influence of LFA-3 density on melanoma cells on lysis and cytokine production (TNF, IL-2, IFN-γ) by T cells following activation by various amounts of antigenic peptides. Our results indicate that increasing LFA-3 density on melanoma cells variably affects their lysis susceptibility, but systematically and considerably enhances cytokine production by melanoma-specific cytotoxic T lymphocyte (CTL) clones. At any stimulatory antigen density, LFA-3 increased the fraction of responding cells and/or cytokine amounts produced by individual cells, without affecting TCR down-regulation. These results show that CD2 engagement increases cytokine gene activation essentially by providing to T cells a TCR-independent co-activation signal. From a practical point of view, our data demonstrate that the level of LFA-3 expressed on tumors critically affects cytokine production by specific CTL and thus the efficiency of specific immune reactions mediated by these cells.

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