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V1 T Lymphocytes from B-CLL Patients Recognize ULBP3 Expressed on Leukemic B Cells and Up-Regulated by Trans-Retinoic Acid

¹ Laboratory of Immunology, National Cancer Research Institute, Genoa, Italy; ² Clinical Hematology, Department of Internal Medicine, University of Genoa, Genoa, Italy; ³ Department of Immunology, Eberhard-Karls University, Tuebingen, Germany; ⁴ Laboratory of Immunology and Oncology, Institute for Cancer Research, Candiolo, Italy; and ⁵ Laboratory of Tumor Immunology and ⁶ Department of Oncology, Università Vita Salute and Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele, Milan, Italy

We analyzed 38 untreated patients with chronic lymphocytic leukemia of B-cell type (B-CLL): 24 low-, 8 intermediate-, and 6 high-risk stage. In 15 patients (13 low risk and 2 intermediate risk), circulating V1 T lymphocytes were significantly increased (100 to 300 cells/µL) compared with most intermediate, all high-risk stage, and 15 healthy donors (50 to 100 cells/µL). We studied these V1 T lymphocytes and observed that they proliferated in vitro and produced tumor necrosis factor or IFN- in response to autologous leukemic B cells but not to normal lymphocytes. However, they were unable to kill resting autologous B cells, which lack the MHC-related MIC-A antigen and express low levels of the UL16-binding protein (ULBP) 3 and undetectable levels of ULBP1, ULBP2, and ULBP4. All these molecules are reported ligands for the NKG2D receptor, which is expressed by T cells and activates their cytolytic function. The V1 T lymphocytes studied were able to lyse the ULBP3⁺ C1R B-cell line upon transfection with MIC-A. More importantly, they also lysed autologous B-CLL cells when transcription and expression of MIC-A or up-regulation of ULBP3 were achieved either by activation or by exposure to trans-retinoic acid. The NKG2D receptor expressed on V1 T cells was involved in the recognition of B-CLL. Finally, in six patients with low numbers of circulating V1 T cells and undetectable ULBP3, the disease progressed over 1 year, whereas no progression occurred in patients with high V1 T lymphocytes and detectable/inducible ULBP3. These data suggest that V1 T lymphocytes may play a role in limiting the progression of B-CLL.

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