A Co-Receptor Independent Transgenic Human TCR Mediates Anti-Tumor and Anti-Self Immunity in Mice

• Published in: The Journal of immunology (1950) 2012-07, Vol.189 (4), p.1627-1638
• Main Authors: Mehrotra, Shikhar, Al-Khami, Amir A., Klarquist, Jared, Husain, Shahid, Naga, Osama, Eby, Jonathan M., Murali, Anuradha K., Lyons, Gretchen E., Li, Mingli, Spivey, Natali D., Norell, Håkan, Martins da Palma, Telma, Onicescu, Georgiana, Diaz-Montero, C. Marcela, Garrett-Mayer, Elizabeth, Cole, David J., Le Poole, I. Caroline, Nishimura, Michael I.
• Format: Article
• Language: English
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1103271

Recent advancements in T cell immunotherapy suggest that T cells engineered with high affinity T cell receptors (TCR) can offer better tumor regression. However, whether a high affinity TCR alone is sufficient to control tumor growth, or the T cell subset bearing the TCR is also important remains unclear. Using the human tyrosinase epitope reactive, CD8 independent, high affinity TCR isolated from MHC class-I restricted CD4 + T cells obtained from tumor infiltrating lymphocytes of a metastatic melanoma patient, we developed a novel TCR transgenic mouse with a C57BL/6 background. This HLA-A2 restricted TCR was positively selected on both CD4 + and CD8 + single-positive (SP) cells. However, when the TCR transgenic mouse was developed with an HLA-A2 background, the transgenic TCR was primarily expressed by CD3 + CD4 - CD8 - double-negative (DN) T cells. TIL 1383I TCR transgenic CD4 + , CD8 + and CD4 - CD8 - T cells were functional and retained the ability to control tumor growth without the need for vaccination or cytokine support in vivo . Furthermore, the HLA-A2 + /human tyrosinase TCR double transgenic mice developed spontaneous hair depigmentation and had visual defects that progressed with age. Our data show that the expression of the high affinity TIL 1383I TCR alone in CD3 + T cells is sufficient to control the growth of murine and human melanoma and the presence or absence of CD4 and CD8 co-receptors had little effect on its functional capacity.