title: Kinetic preservation of dual specificity of coprogrammed minor histocompatibility antigen-reactive virus-specific T cells.
abstract: Adoptive transfer of antigen-specific T cells is an attractive strategy for the treatment of hematologic malignancies. It has been shown that T cells recognizing minor histocompatibility antigens (mHag) selectively expressed on hematopoietic cells mediate antileukemic reactivity after allogeneic stem cell transplantation. However, large numbers of T cells with defined specificity are difficult to attain. An attractive strategy to obtain large numbers of leukemia-reactive T cells is retroviral transfer of mHag-specific T-cell receptors (TCR). TCR transfer into T cells specific for persistent viruses may enable these T cells to proliferate both after encountering with viral antigens as well as mHags, increasing the possibility of in vivo survival. We analyzed whether the dual specificity of the TCR-transferred T cells after repetitive stimulation via either the introduced antileukemic HA-2-TCR or the endogenous cytomegalovirus (CMV) specific CMV-TCR was preserved. We show that after repetitive stimulation, T cells skew to a population predominantly expressing the triggered TCR. However, HA-2-TCR-transferred CMV-specific T cells with high antileukemic HA-2-TCR expression but low CMV-TCR expression were able to persist and proliferate after repetitive stimulation with pp65. Moreover, HA-2-TCR-transferred CMV-specific T cells remained dual specific after repetitive stimulation and TCR expression could be reverted after additional stimulation via the previously nonstimulated TCR, restoring high-avidity interactions. These data imply persistence of TCR-transferred virus-specific T cells with both antileukemic and antivirus reactivity in vivo.
authors.affiliation: Department of Hematology, Leiden University Medical Center, Leiden, the Netherlands.
authors.forename: Marleen M
authors.initials: MM
authors.lastname: van Loenen
authors.forename: Renate S
authors.initials: RS
authors.lastname: Hagedoorn
authors.forename: Michel G D
authors.initials: MG
authors.lastname: Kester
authors.forename: Manja
authors.initials: M
authors.lastname: Hoogeboom
authors.forename: Roel
authors.initials: R
authors.lastname: Willemze
authors.forename: J H Frederik
authors.initials: JH
authors.lastname: Falkenburg
authors.forename: Mirjam H M
authors.initials: MH
authors.lastname: Heemskerk
mesh_terms: D003587:Cytomegalovirus / Q000276:immunology*; D006801:Humans; D007700:Kinetics; D015778:Minor Histocompatibility Antigens / Q000276:immunology*; D009363:Neoplasm Proteins / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*
chemical_list: C080145:HA-2 antigen; D015778:Minor Histocompatibility Antigens; D009363:Neoplasm Proteins; D011948:Receptors, Antigen, T-Cell