Functional Inhibitory Receptors Expressed by a Cutaneous T Cell Lymphoma-Specific Cytolytic Clonal T Cell Population

Inhibitory receptors on natural killer cells and on a minority of T lymphocytes are major histocompatibility complex class Ia or Ib specific. We have previously reported several tumor-specific cytotoxic T cell clones infiltrating a CD4+ Vβ13+ cutaneous T cell lymphoma. These clones mediated a specific major histocompatibility complex class I-restricted cytotoxic activity toward the uncultured tumor cells and autologous long-term tumor T cell lines. In this study, we cultured with interleukin-2 the peripheral blood lymphocytes of the same patient a few weeks before invasion of the blood by tumor cells. We report the rapid and selective expansion of a CD8+ Vβ13+ lymphoid population. This population was clonal, as it expressed a unique T cell receptor-Vβ junctional region. Vβ13+ tumor cells and Vβ13+ reactive T cells were shown to have different junctional sequences. The CD8+ reactive clone was functional, as it had a specific autologous tumor-specific, human leukocyte antigen-A2 restricted, cytotoxic activity. This clone coexpressed high levels of CD158a, CD158b, p70, and CD94/NKG2A inhibitory receptors. Interestingly, we found that anti-CD158a and anti-CD158b monoclonal antibodies could inhibit anti-CD3 redirected cytotoxicity mediated by the reactive clonal population. Further, an anti-human leukocyte antigen-B/C monoclonal antibody enhanced the specific cytotoxic activity of the clone against autologous tumor cells. These results are the first evidence that inhibitory receptor expression can lead to the inhibition of cutaneous T cell lymphoma-specific T cell responses