Prolonged (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate-driven antimicrobial and cytotoxic responses of pulmonary and systemic Vγ2Vδ2 T cells in macaques
Prolonged (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate-driven antimicrobial and cytotoxic responses of pulmonary and systemic Vγ2Vδ2 T cells in macaques
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DOI：
10.4049/jimmunol.179.12.8287
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发表时间：
2007-12-15
影响因子：
4.4
通讯作者：
Chen, Zheng W.
中科院分区：
文献类型：
--
作者：
Ali, Zahida;Shao, Lingyan;Chen, Zheng W.
尽管磷酸化抗原特异性V γ 2 V δ 2 T细胞似乎在抗微生物和抗癌免疫中发挥作用，但这些γ δ T细胞在感染或磷脂配体治疗期间的粘膜免疫应答和效应器功能仍然不清楚。在这项研究中，我们证明了微生物磷酸化抗原（E）-4-羟基-3-甲基-丁-2-烯焦磷酸盐（HMBPP）加IL-2治疗猕猴诱导循环V γ 2 V δ 2 T细胞的长期主要扩增，这些T细胞表达CD 8并在其峰值扩增期间产生细胞毒性穿孔素。有趣的是，HMBPP激活的V γ 2 V δ 2 T细胞经历了异常的肺蓄积，其持续3-4个月，尽管循环的V γ 2 V δ 2 T细胞在几周前已经恢复到基线水平。在HMBPP/IL-2联合治疗后，在肺中积累的V γ 2 V δ 2 T细胞显示效应记忆表型，如下：CCR 5（+）CCR 7（-）CD 45 RA（-）CD 27（+），并且能够重新识别磷抗原，并在治疗后长达15周产生大量IFN-γ。此外，大量扩增的V γ 2 V δ 2 T细胞在体内产生细胞因子的能力与HMBPP/IL-2共处理后CD 4（+）和CD 8（+）α β T细胞数量的增加以及CD 3（+）V γ 2（-）T细胞的大量穿孔素表达一致。因此，肺和全身V γ 2 V δ 2 T细胞的延长的HMBPP驱动的抗微生物和细胞毒性应答可以赋予针对感染性疾病和癌症的免疫治疗剂。
Although phosphoantigen-specific V gamma 2V delta 2 T cells appear to play a role in antimicrobial and anticancer immunity, mucosal immune responses and effector functions of these gamma delta T cells during infection or phospholigand treatment remain poorly characterized. In this study, we demonstrate that the microbial phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) plus IL-2 treatment of macaques induced a prolonged major expansion of circulating V gamma 2V delta 2 T cells that expressed CD8 and produced cytotoxic perforin during their peak expansion. Interestingly, HMBPP-activated V gamma 2V delta 2 T cells underwent an extraordinary pulmonary accumulation, which lasted for 3-4 mo, although circulating V gamma 2V delta 2 T cells had returned to baseline levels weeks prior. The V gamma 2V delta 2 T cells that accumulated in the lung following HMBPP/IL-2 cotreatment displayed an effector memory phenotype, as follows: CCR5(+)CCR7(-)CD45RA(-)CD27(+) and were able to re-recognize phosphoantigen and produce copious amounts of IFN-gamma up to 15 wk after treatment. Furthermore, the capacity of massively expanded V gamma 2V delta 2 T cells to produce cytokines in vivo coincided with an increase in numbers of CD4(+) and CD8(+) alpha beta T cells after HMBPP/IL-2 cotreatment as well as substantial perforin expression by CD3(+)V gamma 2(-) T cells. Thus, the prolonged HMBPP-driven antimicrobial and cytotoxic responses of pulmonary and systemic V gamma 2V delta 2 T cells may confer immunotherapeutics against infectious diseases and cancers.