Tumor escape mechanisms from immunosurveillance: induction of unresponsiveness in a specific MHC-restricted CD4+ human T cell clone by the autologous MHC class II+ melanoma.
The co-existence of tumor specific immunity with a progressing tumor is observed in a variety of experimental systems and remains one of the major paradoxes of tumor immunology. We now report that a human melanoma cell line (SMC) expressing MHC class II was able to induce clonal anergy in a specific, MHC-restricted CD4+ T cell clone (STC3). Clonal anergy is a mechanism of T lymphocyte tolerance induced by antigen receptor stimulation in the absence of co-stimulation. We observed that a CD4+ T cell clone and an autologous melanoma cell line form conjugates with each other that leads to an increase of [Ca++]i in the T cell clone; however, this interaction failed to induce IL-2 production or proliferation of the T cell clone. Furthermore, this interaction rendered this T cell clone unresponsive to subsequent stimulation. All these effects were MHC class II restricted. Therefore, the human melanoma cell line SMC was capable of delivering antigen-specific signals to the T cell clone, but did not deliver the co-stimulatory signals, e.g. a B7/CD28 interaction, necessary for full T cell activation. Transfection of the melanoma cells with an expression vector containing a B7 cDNA that resulted in subsequent expression of B7 on its cell surface rendered it into a fully competent antigen presenting cell, which is able to induce a nuclear factor binding to the IL-2 promoter in the specific T cell clone resulting in enhanced IL-2 transcription, synthesis, and T cell proliferation. These findings suggest that manipulation of co-stimulation may offer new strategies for future tumor immunotherapy.
Becker
J C
JC
Institute of Dermatology, University of Würzburg, Germany.
Brabletz
T
T
Czerny
C
C
Termeer
C
C
Bröcker
E B
EB
D001483:Base Sequence; D015152:Blotting, Northern; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002460:Cell Line; D017635:Clonal Anergy / Q000502:physiology*; D006684:HLA-DR Antigens / Q000502:physiology*; D006801:Humans; D007157:Immunologic Surveillance; D007376:Interleukin-2 / Q000032:analysis; D016246:Lymphocytes, Tumor-Infiltrating / Q000502:physiology; D008545:Melanoma / Q000276:immunology*; D008969:Molecular Sequence Data; D012333:RNA, Messenger / Q000032:analysis; D014162:Transfection; D014407:Tumor Cells, Cultured
D006684:HLA-DR Antigens; D007376:Interleukin-2; D012333:RNA, Messenger; D002118:Calcium