Induction of tolerance and immunity by redirected B cell-specific cytolytic T lymphocytes

Chimeric receptors bearing ligand recognition domains linked to signaling regions from the T-cell receptor can redirect T lymphocytes against non-MHC-restricted targets. Cytolytic T lymphocytes (CTL) expressing these chimeric receptors are being tested in preclinical and clinical trials for activity in cancer, infectious diseases and autoimmunity. The chimeric receptors may incorporate antigenic epitopes previously unrecognized by the immune system. Whether a receptor-specific antibody response develops to these neoantigens and whether such a response inhibits therapeutic cell activity is unknown. We hypothesized that upon engagement of a chimeric receptor-specific B cell, receptor-modified CTL will be activated, lysing the B cell and inducing tolerance to the chimeric receptor rather than immunity. We demonstrate that receptor-modified CTL are indeed stimulated by cognate receptor-specific B cells, proliferate and produce cytokines in response and kill the B cells in vitro and in vivo. However, this is insufficient to induce full B-cell tolerance. Modified CTL induce a chimeric receptor-specific antibody response independent of any other source of antigen. Nevertheless, the CTL retain substantial activity even in the presence of saturating doses of receptor-specific antibody. Thus antichimeric receptor antibody responses need to be considered in the clinical use of chimeric receptor-modified T cells. However, the inhibitory activity of these antibodies may in cases be limited.