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Transgenic Expression of Ly49A on T Cells Impairs a Specific Antitumor Response¹

Pierre Brawand^*, François A. Lemonnier, H. Robson MacDonald^*, Jean-Charles Cerottini^* and Werner Held^2,*

^* Ludwig Institute for Cancer Research, Lausanne Branch, University of Lausanne, Epalinges, Switzerland; and Unité d’Immunité Cellulaire Antivirale, Département SIDA-Rétrovirus, Institut Pasteur, Paris, France

Inhibitory MHC receptors determine the reactivity and specificity of NK cells. These receptors can also regulate T cells by modulating TCR-induced effector functions such as cytotoxicity, cytokine production, and proliferation. Here we have assessed the capacity of mouse T cells expressing the inhibitory MHC class I receptor Ly49A to respond to a well-defined tumor Ag in vivo using Ly49A transgenic mice. We find that the presence of Ly49A on the vast majority of lymphocytes prevents the development of a significant Ag-specific CD8⁺ T cell response and, consequently, the rejection of the tumor. Despite minor alterations in the TCR repertoire of CD8⁺ T cells in the transgenic lines, precursors of functional tumor-specific CD8⁺ T cells exist but could not be activated most likely due to a lack of appropriate CD4⁺ T cell help. Surprisingly, all of these effects are observed in the absence of a known ligand for the Ly49A receptor as defined by its ability to regulate NK cell function. Indeed, we found that the above effects on T cells may be based on a weak interaction of Ly49A with K^b or D^b class I molecules. Thus, our data demonstrate that enforced expression of a Ly49A receptor on conventional T cells prevents a specific immune response in vivo and suggest that the functions of T and NK cells are differentially sensitive to the presence of inhibitory MHC class I receptors.

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