生物钟影响免疫效率 ZT

Summary: CD8 T cells function differently, according to the time of day. Study shows how the biological clock influences immune response.

https://neurosciencenews.com/circadian-clock-immune-response-14973/amp/

Biological clock influences immune response efficiency

Abstract

The circadian clock of CD8 T cells modulates their early response to vaccination and the rhythmicity of related signaling pathways

Circadian variations of various aspects of the immune system have been described. However, the circadian control of T cells has been relatively unexplored. Here, we investigated the role of circadian clocks in regulating CD8 T cell response to antigen presentation by dendritic cells (DCs). The in vivo CD8 T cell response following vaccination with DCs loaded with the OVA257–264 peptide antigen (DC-OVA) leads to a higher expansion of OVA-specific T cells in response to vaccination done in the middle of the day, compared to other time points. This rhythm was dampened when DCs deficient for the essential clock gene Bmal1 were used and abolished in mice with a CD8 T cell-specific Bmal1 deletion. Thus, we assessed the circadian transcriptome of CD8 T cells and found an enrichment in the daytime of genes and pathways involved in T cell activation. Based on this, we investigated early T cell activation events. Three days postvaccination, we found higher T cell activation markers and related signaling pathways (including IRF4, mTOR, and AKT) after a vaccination done during the middle of the day compared to the middle of the night. Finally, the functional impact of the stronger daytime response was shown by a more efficient response to a bacterial challenge at this time of day. Altogether, these results suggest that the clock of CD8 T cells modulates the response to vaccination by shaping the transcriptional program of these cells and making them more prone to strong and efficient activation and proliferation according to the time of day.

 

以往有关报道（中文版）

Science特刊：失眠、肥胖、癌症……万能的生物钟如何掌管我们的身体？

https://www.biodiscover.com/news/research/651038.html

 

Nature子刊：生物钟基因影响自身免疫性疾病严重程度

http://www.biodiscover.com/news/research/727720.html

 

Nature子刊：免疫疗法重大突破

https://med.sina.cn/article_detail_103_2_30030.html

研究人员研究了免疫应答细胞——CD8 + T淋巴细胞的不同亚型间如何配合以增强抗肿瘤免疫反应。研究结果表明，对癌症的最佳免疫应答需要两种类型的记忆T细胞的配合（一种在血液中循环，另一种在组织中循环）。研究结果发表在“自然通讯”杂志，该项研究结果具有改善目前癌症免疫治疗策略的潜力，特别是与预防癌症转移有关。

 

免疫治疗，是一种利用免疫系统对抗癌症的治疗手段，也是一种对抗疾病的革命性治疗手段，被科学杂志选为2013年最主要的科学进步。据该研究领导人David Sancho介绍，“癌症能逃逸免疫系统的控制，是因为可以识别和消除肿瘤细胞的毒性T淋巴细胞被抑制，目前的免疫治疗是基于这些T淋巴细胞的再活化；然而，对于如何更有效地激活这些T淋巴细胞知之甚少，特别是如何触发免疫记忆以预防肿瘤转移的发生。”

 

CNIC研究团队通过使用不同的方法用肿瘤抗原接种以产生特异靶向癌症的细胞毒性记忆T细胞。 取决于接种方法，获得的记忆T淋巴细胞在血液和组织之间循环或存在于组织中并且不再循环。已知在组织中驻留的记忆T细胞在抗病毒再感染方面的有效性，但是迄今为止它们抗肿瘤免疫的贡献是未知的。

 

同时，研究的第一作者Michel Enamorado指出：“我们发现循环和组织驻留记忆细胞合作以产生最佳抗肿瘤免疫反应，组织驻留记忆细胞能够产生重新循环记忆细胞的警戒状态，导致更快更有效的免疫应答。

 

T淋巴细胞的过继转移

 

已经在患者中使用的另一种癌症免疫治疗方法是靶向肿瘤T细胞的过继转移。作者表明过继转移的循环记忆T细胞能够在感染癌症的背景下将自身转化为常驻记忆细胞。此外，通过将这种转移与目前用于受体PD-1抗体的T细胞抗肿瘤反应的临床策略相结合，进一步提高了免疫治疗效率。作者还发现，细胞毒性记忆T细胞抗肿瘤反应的再激活需要树突状细胞的DC1亚型。

 

研究表明，最佳的抗肿瘤免疫反应需要产生循环和组织驻留T细胞记忆。两种记忆T细胞亚型可以用现有的免疫治疗方法重新激活，二者的再激活都需要DC1树突状细胞。癌症免疫治疗不仅仅是可以有效促进原发性肿瘤排斥的治疗方法；而且，它也是手术后阻止原发性肿瘤转移的基础工具。

 

参考文献：Enhanced anti-tumour immunity requires the interplay between resident and circulating memory CD8 T cells. Nature Communications, 2017; 8: 16073