Signaling through MHC in transgenic mice generates a population of memory phenotype cytolytic cells that lack TCR

• Published in: Blood Vol. 101; no. 11; pp. 4520 - 4528
• Main Authors: McFarland, Hugh I., Hansal, Susan A., Morris, Diane I., McVicar, Daniel W., Love, Paul E., Rosenberg, Amy S.
• Format: Journal Article
• Language: English
• Published: Washington, DC Elsevier Inc 01-06-2003; The Americain Society of Hematology
• Subjects: Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Animals; Applied cell therapy and gene therapy; Biological and medical sciences; Cytotoxicity, Immunologic; Histocompatibility Antigens Class I - immunology; Humans; Immunologic Memory; Immunophenotyping; Medical sciences; Mice; Mice, Transgenic; Receptors, Antigen, T-Cell - deficiency; Recombinant Fusion Proteins; Signal Transduction; T-Lymphocyte Subsets - immunology; T-Lymphocytes, Cytotoxic - immunology; Thymus Gland - cytology; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Tumor Cells, Cultured; Immunopathology; Animal model; T cell receptor; Cell therapy; Immunophenotype; Stem cell; Major histocompatibility system; Rodentia; Transgenic animal; Hematopoietic cell; Homograft; Graft versus host reaction; Immune regulation; Memory lymphocyte; Vertebrata; Mammalia; Mouse; Zéta-Peptide chain; Graft; Fusion protein; Cytotoxic T lymphocyte; Class I histocompatibility antigen
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2002-10-3265

We constructed a chimeric molecule, composed of the T-cell receptor (TCR)–ζ chain fused to the extracellular domains of a prototypical allogeneic major histocompatibility complex (MHC) class I molecule, Dd, to assess whether such a construct could affect Dd allospecific responses in vitro and in vivo. To generate cytotoxic T lymphocytes (CTLs) expressing the construct, Dd-ζ was targeted to lymphocyte populations in transgenic mice by placing its expression under control of the CD2 promoter. In response to ligation of Dd, lymphocytes from transgenic mice expressing high levels of Dd-ζ are activated to proliferate and kill cells binding to Dd, despite the near total loss of CD8+ T cells in these mice. Thus, the Dd-ζ cytolytic cell was found not to be a conventional CD8+ CTL, but rather an unusual T lineage cell (CD3-CD5+Thy1.1+) that lacked αβ or γδ TCRs, as well as CD4 and CD8 coreceptors, but expressed surface markers strikingly similar to memory CTLs, including CD44, Ly-6C, and CD122. These cells originate in the thymus and potently veto responses to Dd in vitro. Lacking TCRs, these veto cells are unlikely to mediate graft-versus-host disease (GVHD) and thus may be useful as a cellular therapy for therapeutic deletion of alloreactive T cells in the settings of graft rejection and GVHD.