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

Authors: 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.; Martins da Palma, T.; Onicescu, G.; Diaz-Montero, C. M.; Garrett-Mayer, E; Cole, D. J.; Le Poole, I. C.; Nishimura, M. I.
Article Title: A coreceptor-independent transgenic human TCR mediates anti-tumor and anti-self immunity in mice
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.
Journal Title: Journal of Immunology
Volume: 189
Issue: 4
ISSN: 1550-6606
Publisher: Unknown  
Journal Place: United States
Date Published: 2012
Start Page: 1627
End Page: 1638
Language: eng
Notes: LR: 20130626; GR: CA104947-S1/CA/NCI NIH HHS/United States; GR: K01 CA134927/CA/NCI NIH HHS/United States; GR: P01 CA154778/CA/NCI NIH HHS/United States; GR: R01 AR057643/AR/NIAMS NIH HHS/United States; GR: R01 CA104947/CA/NCI NIH HHS/United States; GR: R21 AR056524/AR/NIAMS NIH HHS/United States; GR: R21 AR56524/AR/NIAMS NIH HHS/United States; JID: 2985117R; 0 (Antigens, CD3); 0 (HLA-A2 Antigen); 0 (Receptors, Antigen, T-Cell); NIHMS386647; OID: NLM: NIHMS386647 [Available on 08/15/13]; OID: NLM: PMC3674773 [Available on 08/15/13]; PMCR: 2013/08/15 00:00; 2012/07/13 [aheadofprint]; ppublish