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Publication Detail
CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor.
  • Publication Type:
    Journal article
  • Publication Sub Type:
    Journal Article
  • Authors:
    Ghorashian S, Veli├ža P, Chua I, McNicol A-M, Carpenter B, Holler A, Nicholson E, Ahmadi M, Zech M, Xue S-A, Uckert W, Morris E, Chakraverty R, Stauss HJ
  • Publication date:
    01/02/2015
  • Pagination:
    1080, 1089
  • Journal:
    J Immunol
  • Volume:
    194
  • Issue:
    3
  • Status:
    Published
  • Country:
    United States
  • PII:
    jimmunol.1401703
  • Language:
    eng
  • Keywords:
    Adoptive Transfer, Animals, Antigens, Neoplasm, Autoantigens, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cell Communication, Cytotoxicity, Immunologic, Gene Expression, Immune Tolerance, Immunophenotyping, Mice, Mice, Transgenic, Phenotype, Proto-Oncogene Proteins c-mdm2, Receptors, Antigen, T-Cell, Recombinant Fusion Proteins, Transduction, Genetic
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.
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