Signaling through MHC in transgenic mice generates a population of memory phenotype cytolytic cells that lack TCR.
We constructed a chimeric molecule, composed of the T-cell receptor (TCR)-zeta 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-zeta 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-zeta 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-zeta cytolytic cell was found not to be a conventional CD8+ CTL, but rather an unusual T lineage cell (CD3-CD5+Thy1.1+) that lacked alphabeta or gammadelta 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.
McFarland
Hugh I
HI
Division of Therapeutics Proteins, Center for Biologics Evaluation and Research, Food and Drug Admnistration, Bethesda, MD, USA. mcfarlandh@cber.fda.gov
Hansal
Susan A
SA
Morris
Diane I
DI
McVicar
Daniel W
DW
Love
Paul E
PE
Rosenberg
Amy S
AS
D000818:Animals; D003602:Cytotoxicity, Immunologic; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D011948:Receptors, Antigen, T-Cell / Q000172:deficiency*; D011993:Recombinant Fusion Proteins; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D013950:Thymus Gland / Q000166:cytology; D014407:Tumor Cells, Cultured
D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins