CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor

Ghorashian, S.; Veliça, P.; Chua, I.; McNicol, A.; Carpenter, B.; Holler, A.; Nicholson, E.; Ahmadi, M.; Zech, M.; Xue, S.; Uckert, W.; Morris, E.; Chakraverty, R.; Stauss, H.J.

CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor

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Item Type:	Article
Title:	CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor
Creators Name:	Ghorashian, S., Veliça, P., Chua, I., McNicol, A., Carpenter, B., Holler, A., Nicholson, E., Ahmadi, M., Zech, M., Xue, S., Uckert, W., Morris, E., Chakraverty, R. and Stauss, H.J.
Abstract:	Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4(+) T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I-restricted TCR responsible for Ag recognition and tolerance induction in CD8(+) T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I-restricted CD4(+) T cells may enhance the efficacy of therapeutic TCR-engineered CD8(+) T cells and can be readily generated with the same TCR.
Keywords:	Adoptive Transfer, Autoantigens, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Communication, Gene Expression, Genetic Transduction, Immune Tolerance, Immunologic Cytotoxicity, Immunophenotyping, Neoplasm Antigens, Phenotype, Proto-Oncogene Proteins c-mdm2, Recombinant Fusion Proteins, Transgenic Mice, T-Cell Antigen Receptors, Animals, Mice
Source:	Journal of Immunology
ISSN:	0022-1767
Publisher:	American Association of Immunologists
Volume:	194
Number:	3
Page Range:	1080-1089
Date:	1 February 2015
Official Publication:	https://doi.org/10.4049/jimmunol.1401703
PubMed:	View item in PubMed

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