Mixed T cell receptor dimers harbor potentially harmful neoreactivity

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 107; no. 24; pp. 10972 - 10977
• Main Authors: van Loenen, Marleen M., de Boer, Renate, Amir, Avital L., Hagedoorn, Renate S., Volbeda, Gerdien L., Willemze, Roelof, van Rood, Johannes J., Falkenburg, J. H. Frederik, Heemskerk, Mirjam H. M.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 15-06-2010; National Acad Sciences
• Subjects: Adoptive Transfer; Antigens; Biological Sciences; Cell Line; Cysteine - chemistry; Dimerization; Dimers; Gene expression; HLA antigens; HLA Antigens - metabolism; Humans; In Vitro Techniques; Lymphocytes; Molecules; Protein Multimerization; Reactivity; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - genetics; Receptors, Antigen, T-Cell - metabolism; Recombinant Proteins - chemistry; Recombinant Proteins - genetics; Recombinant Proteins - metabolism; Retroviral vectors; T cell antigen receptors; T cell receptors; T-Lymphocytes - immunology; Transduction, Genetic; Tumors; Viruses
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1005802107

Adoptive transfer of T cell receptor (TCR)-transduced T cells may be an attractive strategy to target both hematological malignancies and solid tumors. By introducing a TCR, large numbers of T cells with defined antigen (Ag) specificity can be obtained. However, by introduction of a TCR, mixed TCR dimers can be formed. Besides the decrease in TCR expression of the introduced and endogenous TCR, these mixed TCR dimers could harbor potentially harmful specificities. In this study, we demonstrate that introduction of TCRs resulted in formation of neoreactive mixed TCR dimers, composed of the introduced TCR chains pairing with either the endogenous TCR α or β chain. Neoreactivities observed were HLA class I or class II restricted. Most neoreactive mixed TCR dimers were allo-HLA reactive; however, neoreactive mixed TCR dimers with autoreactive activity were also observed. We demonstrate that inclusion of an extra disulfide bond between the constant domains of the introduced TCR markedly reduced neoreactivity, whereas enhanced effectiveness of the introduced TCR was observed. In conclusion, TCR transfer results in the formation of neoreactive mixed TCR dimers with the potential to generate off-target effects, underlining the importance of searching for techniques to facilitate preferential pairing.