Casetti Rita, Perretta Gemma, Taglioni Alessandra, Mattei Maurizio, Colizzi Vittorio, Dieli Francesco, D'Offizi Gianpiero, Malkovsky Miroslav, Poccia Fabrizio
National Institute for Infectious Diseases, Lazzaro Spallanzani, Istituto di Ricerca e Cura a Carattere Scientifico, Rome, Italy.
J Immunol. 2005 Aug 1;175(3):1593-8. doi: 10.4049/jimmunol.175.3.1593.
Human Vgamma9Vdelta2 T cells recognize nonpeptidic Ags generated by the 1-deoxy-d-xylulose 5-phosphate (many eubacteria, algae, plants, and Apicomplexa) and mevalonate (eukaryotes, archaebacteria, and certain eubacteria) pathways of isoprenoid synthesis. The potent Vgamma9Vdelta2 T cell reactivity 1) against certain cancer cells or 2) induced by infectious agents indicates that therapeutic augmentations of Vgamma9Vdelta2 T cell activities may be clinically beneficial. The functional characteristics of Vgamma9Vdelta2 T cells from Macaca fascicularis (cynomolgus monkey) are very similar to those from Homo sapiens. We have found that the i.v. administration of nitrogen-containing bisphosphonate or pyrophosphomonoester drugs into cynomolgus monkeys combined with s.c. low-dose (6 x 10(5) U/animal) IL-2 induces a large pool of CD27+ and CD27- effector/memory T cells in the peripheral blood of treated animals. The administration of these drugs in the absence of IL-2 is substantially less effective, indicating the importance of additional exogenous costimuli. Shortly after the costimulatory IL-2 treatment, only gammadelta (but not alphabeta) T cells expressed the CD69 activation marker, indicating that Vgamma9Vdelta2 T lymphocytes are more responsive to low-dose IL-2 than alphabeta T cells. Up to 100-fold increases in the numbers of peripheral blood Vgamma9Vdelta2 T cells were observed in animals receiving the gammadelta stimulatory drug plus IL-2. Moreover, the expanded Vgamma9Vdelta2 T cells were potent Th1 effectors capable of releasing large amounts of IFN-gamma. These results may be relevant for designing novel (or modifying current) immunotherapeutic trials with nitrogen-containing bisphosphonate or pyrophosphomonoester drugs.
人类Vγ9Vδ2 T细胞可识别由异戊二烯合成的1-脱氧-D-木酮糖5-磷酸途径（许多真细菌、藻类、植物和顶复门原虫）和甲羟戊酸途径（真核生物、古细菌和某些真细菌）产生的非肽抗原。Vγ9Vδ2 T细胞的强大反应性：1）针对某些癌细胞；2）由感染因子诱导，这表明增强Vγ9Vδ2 T细胞活性的治疗方法可能具有临床益处。食蟹猴的Vγ9Vδ2 T细胞的功能特性与人类的非常相似。我们发现，向食蟹猴静脉注射含氮双膦酸盐或焦磷酸单酯药物，并皮下注射低剂量（6×10⁵ U/只动物）白细胞介素-2，可在接受治疗动物的外周血中诱导产生大量CD27⁺和CD27⁻效应/记忆T细胞。在没有白细胞介素-2的情况下给予这些药物，效果要差得多，这表明额外的外源性共刺激的重要性。在共刺激白细胞介素-2治疗后不久，只有γδ（而非αβ）T细胞表达CD69激活标志物，这表明Vγ9Vδ2 T淋巴细胞比αβ T细胞对低剂量白细胞介素-2更敏感。在接受γδ刺激药物加白细胞介素-2的动物中，外周血Vγ9Vδ2 T细胞数量增加了多达100倍。此外，扩增后的Vγ9Vδ2 T细胞是强大的Th1效应细胞，能够释放大量干扰素-γ。这些结果可能与设计含氮双膦酸盐或焦磷酸单酯药物的新型（或改进现有）免疫治疗试验相关。
