Vdelta1 T lymphocytes from B-CLL patients recognize ULBP3 expressed on leukemic B cells and up-regulated by trans-retinoic acid.
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 Vdelta1 T lymphocytes were significantly increased (100 to 300 cells/muL) compared with most intermediate, all high-risk stage, and 15 healthy donors (50 to 100 cells/muL). We studied these Vdelta1 T lymphocytes and observed that they proliferated in vitro and produced tumor necrosis factor alpha or IFN-gamma 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 gammadelta T cells and activates their cytolytic function. The Vdelta1 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 Vdelta1 T cells was involved in the recognition of B-CLL. Finally, in six patients with low numbers of circulating Vdelta1 T cells and undetectable ULBP3, the disease progressed over 1 year, whereas no progression occurred in patients with high Vdelta1 T lymphocytes and detectable/inducible ULBP3. These data suggest that Vdelta1 T lymphocytes may play a role in limiting the progression of B-CLL.
Poggi
Alessandro
A
Laboratory of Immunology, National Cancer Research Institute, Genoa, Italy.
Venturino
Claudia
C
Catellani
Silvia
S
Clavio
Marino
M
Miglino
Maurizio
M
Gobbi
Marco
M
Steinle
Alexander
A
Ghia
Paolo
P
Stella
Stefania
S
Caligaris-Cappio
Federico
F
Zocchi
Maria Raffaella
MR
D000368:Aged; D000369:Aged, 80 and over; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D002352:Carrier Proteins / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D018920:Coculture Techniques; D005260:Female; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis / Q000235:genetics / Q000276:immunology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins; D007371:Interferon-gamma / Q000096:biosynthesis; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000188:drug therapy / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014212:Tretinoin / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D015854:Up-Regulation / Q000187:drug effects
D002352:Carrier Proteins; D058851:GPI-Linked Proteins; D015395:Histocompatibility Antigens Class I; D036341:Intercellular Signaling Peptides and Proteins; C099187:MHC class I-related chain A; D012333:RNA, Messenger; D016692:Receptors, Antigen, T-Cell, gamma-delta; D014409:Tumor Necrosis Factor-alpha; C423229:ULBP3 protein, human; D014212:Tretinoin; D007371:Interferon-gamma