自然殺傷T淋巴細(xì)胞（natural killer T cells,，NKT細(xì)胞）是一類同時(shí)表達(dá)恒定的T淋巴細(xì)胞受體（TCR）αβ（人為Vα24/Vβ11,，鼠為Vα14/Vβ8）和NK細(xì)胞標(biāo)志的T細(xì)胞亞群，主要經(jīng)抗原提呈細(xì)胞表面CD1d提呈的糖脂類抗原活化,，并迅速地釋放大量的IFNγ和IL-4等細(xì)胞因子,，通過調(diào)節(jié)Th1/Th2細(xì)胞間的平衡，在自身免疫性疾病,、抗感染,、抗腫瘤等方面發(fā)揮重要的作用。
Vα24恒定表達(dá)的NKT細(xì)胞通過靶向腫瘤相關(guān)巨噬細(xì)胞(TAMs)來抑制腫瘤生長(zhǎng),。因此,，腫瘤的演進(jìn)依賴于TAMs逃避NKT細(xì)胞的殺傷性作用，但是該作用的潛在機(jī)制目前還不明確,。
近日,，來自美國(guó)貝勒醫(yī)學(xué)院的研究人員Leonid S. Metelitsa等人發(fā)現(xiàn)，IL-15能夠保護(hù)NKT細(xì)胞免受TAMs對(duì)它的抑制作用,，并增強(qiáng)其抗轉(zhuǎn)移活性,。相關(guān)論文發(fā)表在5月8日的The Journal of Clinical Investigation。
他們發(fā)現(xiàn),，來自成神經(jīng)細(xì)胞瘤(NB)細(xì)胞系及原發(fā)腫瘤的一些細(xì)胞表達(dá)了膜結(jié)合型的TNF-α(mbTNF-α),。這些促炎性腫瘤細(xì)胞通過激活NF-κB信號(hào)通路，誘導(dǎo)了腫瘤相關(guān)巨噬細(xì)胞趨化因子CCL20的產(chǎn)生,，而且這種作用在低氧情況下會(huì)被放大,。
利用流式細(xì)胞術(shù)分析人類原發(fā)性成神經(jīng)細(xì)胞瘤，他們發(fā)現(xiàn),，CCL20能夠在腫瘤相關(guān)巨噬細(xì)胞內(nèi)選擇性積累,。
在體外，對(duì)趨化因子的中和能夠抑制NKT細(xì)胞遷移到缺氧的單核細(xì)胞,；在小鼠,，中和趨化因子也抑制了NKT細(xì)胞定位到移植的成神經(jīng)細(xì)胞瘤。
他們還發(fā)現(xiàn),，缺氧損傷了NKT細(xì)胞的活性及功能,。為此Leonid S. Metelitsa表示,，產(chǎn)生CCL20的TAMs可以對(duì)腫瘤浸潤(rùn)的NKT細(xì)胞產(chǎn)生一個(gè)缺氧陷阱（hypoxic trap）的作用。
結(jié)果表明,，IL-15保護(hù)了抗原激活的NKT細(xì)胞免受缺氧傷害,。有趣的是，在老鼠模型,，轉(zhuǎn)基因表達(dá)IL-15的NKT細(xì)胞的抗遷移活性顯著增加,。（生物谷Deepblue編譯）
doi: 10.1172/JCI59535
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IL-15 protects NKT cells from inhibition by tumor-associated macrophages and enhances antimetastatic activity
Daofeng Liu, Liping Song, Jie Wei, Amy N. Courtney, Xiuhua Gao, Ekaterina Marinova, Linjie Guo, Andras Heczey, Shahab Asgharzadeh, Eugene Kim1, Gianpietro Dotti and Leonid S. Metelitsa.
Vα24-invariant NKT cells inhibit tumor growth by targeting tumor-associated macrophages (TAMs). Tumor progression therefore requires that TAMs evade NKT cell activity through yet-unknown mechanisms.Here we report that a subset of cells in neuroblastoma (NB) cell lines and primary tumors expresses membrane-bound TNF-α (mbTNF-α).These proinflammatory tumor cells induced production of the chemokine CCL20 from TAMs via activation of the NF-κB signaling pathway, an effect that was amplified in hypoxia. Flow cytometry analyses of human primary NB tumors revealed selective accumulation of CCL20 in TAMs.Neutralization of the chemokine inhibited in vitro migration of NKT cells toward tumor-conditioned hypoxic monocytes and localization of NKT cells to NB grafts in mice.We also found that hypoxia impaired NKT cell viability and function. Thus, CCL20-producing TAMs served as a hypoxic trap for tumor-infiltrating NKT cells.IL-15 protected antigen-activated NKT cells from hypoxia, and transgenic expression of IL-15 in adoptively transferred NKT cells dramatically enhanced their antimetastatic activity in mice.Thus, tumor-induced chemokine production in hypoxic TAMs and consequent chemoattraction and inhibition of NKT cells represents a mechanism of immune escape that can be reversed by adoptive immunotherapy with IL-15–transduced NKT cells
