A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice

Shikhar Mehrotra*, Amir A. Al-Khami, Jared Klarquist, Shahid Husain, Osama Naga, Jonathan M. Eby, Anuradha K. Murali, Gretchen E. Lyons, Mingli Li, Natali D. Spivey, Håkan Norell, Telma Martins Da Palma, Georgiana Onicescu, C. Marcela Diaz-Montero, Elizabeth Garrett-Mayer, David J. Cole, I. Caroline Le Poole, Michael I. Nishimura

*Corresponding author for this work

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Recent advancements in T cell immunotherapy suggest that T cells engineered with high-affinity 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 (TIL) 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 cells. However, when the TCR transgenic mouse was developed with a HLA-A2 background, the transgenic TCR was primarily expressed by CD3 +CD4 -CD8 - double-negative 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 coreceptors had little effect on its functional capacity.

Original languageEnglish (US)
Pages (from-to)1627-1638
Number of pages12
JournalJournal of Immunology
Volume189
Issue number4
DOIs
StatePublished - Aug 15 2012

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

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    Mehrotra, S., Al-Khami, A. A., Klarquist, J., Husain, S., Naga, O., Eby, J. M., Murali, A. K., Lyons, G. E., Li, M., Spivey, N. D., Norell, H., Da Palma, T. M., Onicescu, G., Diaz-Montero, C. M., Garrett-Mayer, E., Cole, D. J., Le Poole, I. C., & Nishimura, M. I. (2012). A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice. Journal of Immunology, 189(4), 1627-1638. https://doi.org/10.4049/jimmunol.1103271