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Ex Vivo Expansion of CD8⁺CD56⁺ and CD8⁺CD56^- Natural Killer T Cells Specific for MUC1 Mucin

¹ VA Medical Center, Atlanta, Georgia; ² OED & Associates, Hermann, Missouri; and Departments of ³ Pathology, ⁴ Urology, and ⁵ Biochemistry and Microbiology & Immunology Emory University, Atlanta, Georgia

Prostate cancers express MUC1, but nearly all metastatic cells lack HLA class I molecules. Thus, a lymphocyte population that can sense its antigenic environment, while also able to react to stimuli of natural killer (NK) cells, may be a more versatile effector cell population for antitumor immune responses. Herein, we report that tumor-specific MUC1 peptide, interleukin 2, and interleukin 12 act synergistically to stimulate the ex vivo expansion of CD8⁺CD56^- T cells and CD8⁺CD56⁺ natural killer T (NKT) cells from the peripheral blood mononuclear cells of prostate cancer patients, as well as healthy male and female donors. Both the CD56⁺ NKT cells and CD56^- T cells lysed allogeneic mucin-bearing target cells, as well as NK target cells, but not lymphokine-activated killer target cells. However, the CD56⁺ NKT cells displayed a 2-fold greater cytolytic activity than the CD56^- T cells. The mucin-specific cytolytic activity and NK cytolytic activities for both lymphocyte populations were independent of HLA class I and CD1 molecules. The CD56^- T cells up-regulated CD56 with continued antigenic stimulation in the presence of interleukin 12, suggesting that CD8⁺CD56^- T cells are NKT cells. However, CD56⁺ NKT cells expand poorly to continued stimulation. All mucin-stimulated NKT cells exhibited the activated/memory CD45RO phenotype. The NKT cell lines express the /ß T-cell receptor (TCR). The TCR repertoire was limited and varied with cell line, but was not the V24Vß11 TCR typically associated with NKT cells. Whereas CD161 is generally considered a marker of NKT cells, the mucin-stimulated NKT cells did not express this marker. Thus, we have described two phenotypically distinct NKT types that do not display a biased TCR repertoire, but do display specificity for a tumor-specific peptide antigen (CTL-like activity), as well as HLA class I-deficient target cells (NK-like activity).

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