Alpha beta T cell receptor transfer to gamma delta T cells generates functional effector cells without mixed TCR dimers in vivo.
The successful application of T cell-based immunotherapeutic applications depends on the availability of large numbers of T cells with the desired Ag specificity and phenotypic characteristics. Engineering of TCR-transferred T lymphocytes is an attractive strategy to obtain sufficient T cells with an Ag specificity of choice. However, the introduction of additional TCR chains into T cells leads to the generation of T cells with unknown specificity, due to the formation of mixed dimers between the endogenous and introduced TCR chains. The formation of such potentially autoaggressive T cells may be prevented by using gammadelta T cells as recipient cells, but the in vivo activity of such TCR-engineered gammadelta T cells has not been established. In the present study, we have investigated the in vivo functionality of TCR-transduced gammadelta T cells, in particular their Ag specific proliferative capacity, Ag specific reactivity, in vivo persistence, and their capacity to mount recall responses. The results demonstrate that alphabeta TCR engineering of gammadelta T cells forms a feasible strategy to generate Ag-specific effector T cells that do not express mixed TCR dimers. In view of increasing concerns on the potential autoimmune consequences of mixed TCR dimer formation, the testing of alphabeta TCR engineered gammadelta T cells in clinical trials seems warranted.
van der Veken
Lars T
LT
Laboratory of Experimental Hematology, Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands.
Coccoris
Miriam
M
Swart
Erwin
E
Falkenburg
J H Frederik
JH
Schumacher
Ton N
TN
Heemskerk
Mirjam H M
MH
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism* / Q000637:transplantation; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D002478:Cells, Cultured; D007156:Immunologic Memory / Q000235:genetics; D016219:Immunotherapy, Adoptive; D007262:Infusions, Intravenous; D007413:Intestinal Mucosa / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D055503:Protein Multimerization; D016693:Receptors, Antigen, T-Cell, alpha-beta / Q000008:administration & dosage* / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000008:administration & dosage* / Q000235:genetics; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014161:Transduction, Genetic / Q000379:methods
D016693:Receptors, Antigen, T-Cell, alpha-beta; D016692:Receptors, Antigen, T-Cell, gamma-delta