PDF(Pubmed)
Abstract：
Aging is usually accompanied by functional declines of the immune system, especially in T-cell responses. However, little is known about ways to alleviate this.
Here, 37 middle-aged healthy participants were recruited, among which 32 were intravenously administrated with expanded NK cells and 5 with normal saline. Then, we monitored changes of peripheral senescent and exhausted T cells within 4 weeks after infusion by flow cytometry, as well as serum levels of senescence-associated secretory phenotype (SASP)-related factors. In vitro co-culture assays were performed to study NK-mediated cytotoxic activity against senescent or exhausted T cells. Functional and phenotypic alteration of NK cells before and after expansion was finally characterized.
After NK cell infusion, senescent CD28-, CD57+, CD28-CD57+, and CD28-KLRG1+ CD4+ and CD8+ T-cell populations decreased significantly, so did PD-1+ and TIM-3+ T cells. These changes were continuously observed for 4 weeks. Nevertheless, no significant changes were observed in the normal saline group. Moreover, SASP-related factors including IL-6, IL-8, IL-1α, IL-17, MIP-1α, MIP-1β, and MMP1 were significantly decreased after NK cell infusion. Further co-culture assays showed that expanded NK cells specifically and dramatically eliminated senescent CD4+ T cells other than CD28+CD4+ T cells. They also showed improved cytotoxic activity, with different expression patterns of activating and inhibitory receptors including NKG2C, NKG2A, KLRG1, LAG3, CD57, and TIM3.
Our findings imply that T-cell senescence and exhaustion is a reversible process in healthy individuals, and autologous NK cell administration can be introduced to alleviate the aging.
ClinicalTrials.gov, ChiCTR-OOh-17011878.
Here, 37 middle-aged healthy participants were recruited, among which 32 were intravenously administrated with expanded NK cells and 5 with normal saline. Then, we monitored changes of peripheral senescent and exhausted T cells within 4 weeks after infusion by flow cytometry, as well as serum levels of senescence-associated secretory phenotype (SASP)-related factors. In vitro co-culture assays were performed to study NK-mediated cytotoxic activity against senescent or exhausted T cells. Functional and phenotypic alteration of NK cells before and after expansion was finally characterized.
After NK cell infusion, senescent CD28-, CD57+, CD28-CD57+, and CD28-KLRG1+ CD4+ and CD8+ T-cell populations decreased significantly, so did PD-1+ and TIM-3+ T cells. These changes were continuously observed for 4 weeks. Nevertheless, no significant changes were observed in the normal saline group. Moreover, SASP-related factors including IL-6, IL-8, IL-1α, IL-17, MIP-1α, MIP-1β, and MMP1 were significantly decreased after NK cell infusion. Further co-culture assays showed that expanded NK cells specifically and dramatically eliminated senescent CD4+ T cells other than CD28+CD4+ T cells. They also showed improved cytotoxic activity, with different expression patterns of activating and inhibitory receptors including NKG2C, NKG2A, KLRG1, LAG3, CD57, and TIM3.
Our findings imply that T-cell senescence and exhaustion is a reversible process in healthy individuals, and autologous NK cell administration can be introduced to alleviate the aging.
ClinicalTrials.gov, ChiCTR-OOh-17011878.
摘要：
衰老通常伴随着免疫系统的功能下降，特别是在T细胞反应中。然而,对缓解这种情况的方法知之甚少。
这里,招募了37名中年健康参与者，其中32例静脉注射扩增的NK细胞，5例静脉注射生理盐水。然后，我们通过流式细胞术监测外周衰老和耗尽T细胞在输注后4周内的变化，以及衰老相关分泌表型（SASP）相关因子的血清水平。进行体外共培养测定以研究NK介导的针对衰老或耗竭T细胞的细胞毒性活性。最终表征了NK细胞在扩增前后的功能和表型改变。
NK细胞输注后，衰老CD28-，CD57+,CD28-CD57+,CD28-KLRG1+CD4+和CD8+T细胞数量显著减少，PD-1+和TIM-3+T细胞也是如此。连续观察这些变化4周。然而，生理盐水组无明显变化。此外，SASP相关因素包括IL-6、IL-8、IL-1α、IL-17，MIP-1α，MIP-1β,NK细胞输注后MMP1明显下降。进一步的共培养试验表明,扩增的NK细胞特异性地和显著地消除了除CD28+CD4+T细胞以外的衰老CD4+T细胞。它们还显示出改善的细胞毒活性，具有不同的表达模式的激活和抑制受体，包括NKG2C，NKG2A,KLRG1、LAG3、CD57和TIM3。
我们的研究结果表明，健康个体的T细胞衰老和衰竭是一个可逆过程，并可引入自体NK细胞给药来缓解衰老。
ClinicalTrials.gov,ChiCTR-OOh-17011878。
这里,招募了37名中年健康参与者，其中32例静脉注射扩增的NK细胞，5例静脉注射生理盐水。然后，我们通过流式细胞术监测外周衰老和耗尽T细胞在输注后4周内的变化，以及衰老相关分泌表型（SASP）相关因子的血清水平。进行体外共培养测定以研究NK介导的针对衰老或耗竭T细胞的细胞毒性活性。最终表征了NK细胞在扩增前后的功能和表型改变。
NK细胞输注后，衰老CD28-，CD57+,CD28-CD57+,CD28-KLRG1+CD4+和CD8+T细胞数量显著减少，PD-1+和TIM-3+T细胞也是如此。连续观察这些变化4周。然而，生理盐水组无明显变化。此外，SASP相关因素包括IL-6、IL-8、IL-1α、IL-17，MIP-1α，MIP-1β,NK细胞输注后MMP1明显下降。进一步的共培养试验表明,扩增的NK细胞特异性地和显著地消除了除CD28+CD4+T细胞以外的衰老CD4+T细胞。它们还显示出改善的细胞毒活性，具有不同的表达模式的激活和抑制受体，包括NKG2C，NKG2A,KLRG1、LAG3、CD57和TIM3。
我们的研究结果表明，健康个体的T细胞衰老和衰竭是一个可逆过程，并可引入自体NK细胞给药来缓解衰老。
ClinicalTrials.gov,ChiCTR-OOh-17011878。
