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 lck. 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.
Nguyen
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Department of Pathology, St Jude Children's Research Hospital, 332 N Lauderdale St, DT-4047 Memphis, TN 38105, USA.
Geiger
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D000818:Animals; D001327:Autoimmune Diseases / Q000628:therapy*; D016827:CD8 Antigens / Q000235:genetics; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015316:Genetic Therapy / Q000379:methods*; D049452:Green Fluorescent Proteins; D006183:H-2 Antigens / Q000235:genetics*; D007108:Immune Tolerance; D008164:Luminescent Proteins / Q000235:genetics; D008213:Lymphocyte Activation; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D016827:CD8 Antigens; D006183:H-2 Antigens; D008164:Luminescent Proteins; D011948:Receptors, Antigen, T-Cell; D049452:Green Fluorescent Proteins