Dagna Lorenzo, Iellem Andrea, Biswas Priscilla, Resta Davide, Tantardini Francesca, Fortis Claudio, Sabbadini Maria Grazia, D'Ambrosio Daniele, Manfredi Angelo A, Ferrarini Marina
Laboratory of Tumor Immunology, Department of Medicine, Scientific Institute H. San Raffaele, Via Olgettina 60, I-20132 Milan, Italy.
Eur J Immunol. 2002 Oct;32(10):2934-43. doi: 10.1002/1521-4141(2002010)32:10<2934::AID-IMMU2934>3.0.CO;2-6.
Human Vgamma9/Vdelta2(+) T lymphocytes participate in the immune response against intracellular pathogens through the secretion of type-1 cytokines and chemokines and by killing of infected cells. Little is known of the effects by type-2 differentiation of gamma delta cells on these functions. Here, we report that bona fide naive cord blood-derived gamma delta lymphocytes expanded in vitro with the mycobacterial antigen isopentenyl pyrophosphate (IPP) can be differentiated as either type-1 or type-2 cells, in the presence of an appropriate cytokine milieu. Instead, peripheral gamma delta cells from PPD-negative healthy adults displayed a type-1 cytokine profile, i.e. IPP-stimulated secretion of IFN-gamma, but not of IL-4 and IL-10. Moreover, they released the macrophage inflammatory protein (MIP)-1beta, but not IL-8 nor the Th2 chemoattractants I-309 and TARC (thymus and activation-regulated chemokine). This cytokine profile was not significantly affected by in vitro culture in Th2 polarizing conditions. Only in one case out of seven were peripheral gamma delta cells fully differentiated to type-2 lymphocytes, characterized by sustained IL-4 and IL-10 production, along with secretion of substantial amounts of IL-8, I-309 and TARC. Type-2 gamma delta T lymphocytes preferentially expressed the co-stimulatory molecule CD30; conversely, no skewing in chemokine receptor expression was observed. Both polarized populations displayed high levels of CXCR3 in the absence of CCR3, CCR4 and CCR5. Finally, type-1, but not type-2, gamma delta T lymphocytes killed IPP-pulsed U937 cells and displayed elevated perforin content. Overall, our data suggest that type-2 differentiation of gamma delta T lymphocytes profoundly affects both their effector functions and their potential to recruit the appropriate leukocyte subsets to the sites of inflammation.
人Vγ9/Vδ2(+) T淋巴细胞通过分泌1型细胞因子和趋化因子以及杀伤被感染细胞来参与针对细胞内病原体的免疫反应。关于γδ细胞的2型分化对这些功能的影响，目前了解甚少。在此，我们报告，在体外经分枝杆菌抗原异戊烯基焦磷酸（IPP）扩增的真正天然脐带血来源的γδ淋巴细胞，在适当的细胞因子环境中可分化为1型或2型细胞。相反，PPD阴性健康成年人的外周γδ细胞呈现1型细胞因子谱，即IPP刺激后分泌IFN-γ，但不分泌IL-4和IL-10。此外，它们释放巨噬细胞炎性蛋白（MIP）-1β，但不释放IL-8以及Th2趋化因子I-309和TARC（胸腺和活化调节趋化因子）。这种细胞因子谱在Th2极化条件下的体外培养中未受到显著影响。在七例中仅有一例外周γδ细胞完全分化为2型淋巴细胞，其特征为持续产生IL-4和IL-10，同时分泌大量IL-8、I-309和TARC。2型γδ T淋巴细胞优先表达共刺激分子CD30；相反，未观察到趋化因子受体表达的偏移。在不存在CCR3、CCR4和CCR5的情况下，两种极化群体均显示高水平的CXCR3。最后，1型而非2型γδ T淋巴细胞杀伤经IPP脉冲处理的U937细胞并呈现穿孔素含量升高。总体而言，我们的数据表明γδ T淋巴细胞的2型分化深刻影响其效应功能以及将合适的白细胞亚群募集至炎症部位的潜力。
