Transgenic expression of Ly49A on T cells impairs a specific antitumor response

Inhibitory MHC receptors determine the reactivity and specificity of NK cel ls. These receptors can also regulate T cells by modulating TCR-induced eff ector functions such as cytotoxicity, cytokine production, and proliferatio n. Here we have assessed the capacity of mouse T cells expressing the inhib itory MHC class I receptor Ly49A to respond to a well-defined tumor Ag in v ivo using Ly49A transgenic mice. We find that the presence of Ly49A on the vast majority of lymphocytes prevents the development of a significant Ag-s pecific CD8(+) T cell response and, consequently, the rejection of the tumo r. Despite minor alterations in the TCR repertoire of CD8(+) T cells in the transgenic lines, precursors of functional tumor-specific CD8(+) T cells e xist but could not be activated most likely due to a lack of appropriate CD 4(+) T cell help. Surprisingly, all of these effects are observed in the ab sence of a known ligand for the Ly49A receptor as defined by its ability to regulate Ng cell function. Indeed, we found that the above effects on T ce lls may be based on a weak interaction of Ly49A with K-b Or D-b class I mol ecules. Thus, our data demonstrate that enforced expression of a Ly49A rece ptor on conventional T cells prevents a specific immune response in vivo an d suggest that the functions of T and NK cells are differentially sensitive to the presence of inhibitory MHC class I receptors.