A safeguard eliminates T cell receptor gene-modified autoreactive T cells after adoptive transfer.
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.
Kieback
Elisa
E
Max Delbrück Center for Molecular Medicine, Robert-Rössle-Strasse 10, 13092 Berlin, Germany.
Charo
Jehad
J
Sommermeyer
Daniel
D
Blankenstein
Thomas
T
Uckert
Wolfgang
W
D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000941:Antigens / Q000737:chemistry; D002469:Cell Separation; D003165:Complement System Proteins / Q000737:chemistry; D048909:Diabetes Complications / Q000235:genetics; D005260:Female; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D019169:Jurkat Cells; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008957:Models, Genetic; D016271:Proto-Oncogene Proteins c-myc / Q000737:chemistry; D011948:Receptors, Antigen, T-Cell / Q000235:genetics*; D012190:Retroviridae / Q000378:metabolism; D013601:T-Lymphocytes / Q000378:metabolism*
D000941:Antigens; D016271:Proto-Oncogene Proteins c-myc; D011948:Receptors, Antigen, T-Cell; D003165:Complement System Proteins