A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer

doi:10.1073/pnas.0710198105

A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer

*Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany;
^†Charité Universitätsmedizin Berlin, Institute of Immunology, Hindenburgdamm 30, 12200 Berlin, Germany; and
^‡Institute of Biology, Humboldt University of Berlin, Robert-Rössle-Strasse 10, 13092 Berlin, Germany

Edited by Peter K. Vogt, The Scripps Research Institute, La Jolla, CA, and approved November 28, 2007 (received for review October 29, 2007)

Abstract

By transfer of T cell receptor (TCR) genes, antigen specificity of T cells can be redirected to target any antigen. Adoptive transfer of TCR-redirected T cells into patients has shown promising results. However, this immunotherapy bears the risk of autoreactive side effects if the TCR recognizes antigens on self-tissue. Here, we introduce a safeguard based on a TCR-intrinsic depletion mechanism to eliminate autoreactive TCR-redirected T cells in vivo. By the introduction of a 10-aa tag of the human c-myc protein into murine (OT-I, P14) and human (gp100) TCR sequences, we were able to deplete T cells that were transduced with these myc-tagged TCRs with a tag-specific antibody in vitro. T cells transduced with the modified TCR maintained equal properties compared with cells transduced with the wild-type receptor concerning antigen binding and effector function. More importantly, therapeutic in vivo depletion of adoptively transferred T cells rescued mice showing severe signs of autoimmune insulitis from lethal diabetes. This safeguard allows termination of adoptive therapy in case of severe side effects.

Footnotes

^§To whom correspondence should be addressed. E-mail: wuckert{at}mdc-berlin.de
Author contributions: E.K., J.C., T.B., and W.U. designed research; E.K. and D.S. performed research; E.K. and W.U. analyzed data; and E.K. and W.U. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission.
This article contains supporting information online at www.pnas.org/cgi/content/full/0710198105/DC1.