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J Immunol. 2015 Feb 1;194(3):1080-9. doi: 10.4049/jimmunol.1401703. Epub 2014 Dec 24.

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

Author information

1
Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; Transplantation Immunology Group, Department of Haematology, Division of Cancer Studies, University College London, London NW3 2PF, United Kingdom; and.
2
Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
3
Transplantation Immunology Group, Department of Haematology, Division of Cancer Studies, University College London, London NW3 2PF, United Kingdom; and.
4
Institute of Biology, Humboldt University Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
5
Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; h.stauss@ucl.ac.uk.

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.

PMID:
25539815
PMCID:
PMC4298128
DOI:
10.4049/jimmunol.1401703
[Indexed for MEDLINE]
Free PMC Article

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