Antigen-specific targeting of CD8+ T cells with receptor-modified T lymphocytes

Chimeric receptors that link ligand recognition domains, such as antibody Fv fragments, with TCR signaling domains can redirect T lymphocytes against MHC-unrestricted targets. Such receptor-modified T lymphocytes have shown promise in the treatment of infectious diseases and cancer. We hypothesized that receptor-modified T lymphocytes may also be designed to target antigen-specific T cells. We synthesized chimeric receptors consisting of the extracellular and transmembrane domains of the class I MHC H-2K(b) molecule linked to the signaling domains of either TCR-zeta, CD28 and zeta, or CD28, zeta, and Ick. T lymphocytes modified to express these receptors and pulsed with antigenic peptide specifically killed precursor CTL. Cytolysis was efficient, even at effector:target ratios of less than one, and specific, selectively killing antigen-specific precursor CTL among a mixed population of T cells. Cytolysis required activation of the receptor-modified T cells, and did not occur with a signaling-deficient chimeric receptor. In contrast to precursor CTL, differentiated CTL proved resistant to lysis by the receptor-modified T cells. These data demonstrate the feasibility of redirecting T lymphocytes against antigen-specific T cells. Receptor-modified T cells expressing chimeric MHC receptors have potential application in autoimmune and alloimmune diseases.