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, D-d, 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, D-d-zeta was targeted to lymphocyte populations in transgenic mice by placing its expression under control of the CD2 promoter. In response to ligation of D-d, lymphocytes from transgenic mice expressing high levels of D-d-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 D-d-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 D-d 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. (C) 2003 by The American Society of Hematology.

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