生物鍾影響免疫效率 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.

 

以往有關報道（中文版）

Science特刊：失眠、肥胖、癌症……萬能的生物鍾如何掌管我們的身體？

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

 

Nature子刊：生物鍾基因影響自身免疫性疾病嚴重程度

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

 

Nature子刊：免疫療法重大突破

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

研究人員研究了免疫應答細胞——CD8 + T淋巴細胞的不同亞型間如何配合以增強抗腫瘤免疫反應。研究結果表明，對癌症的最佳免疫應答需要兩種類型的記憶T細胞的配合（一種在血液中循環，另一種在組織中循環）。研究結果發表在“自然通訊”雜誌，該項研究結果具有改善目前癌症免疫治療策略的潛力，特別是與預防癌症轉移有關。

 

免疫治療，是一種利用免疫係統對抗癌症的治療手段，也是一種對抗疾病的革命性治療手段，被科學雜誌選為2013年最主要的科學進步。據該研究領導人David Sancho介紹，“癌症能逃逸免疫係統的控製，是因為可以識別和消除腫瘤細胞的毒性T淋巴細胞被抑製，目前的免疫治療是基於這些T淋巴細胞的再活化；然而，對於如何更有效地激活這些T淋巴細胞知之甚少，特別是如何觸發免疫記憶以預防腫瘤轉移的發生。”

 

CNIC研究團隊通過使用不同的方法用腫瘤抗原接種以產生特異靶向癌症的細胞毒性記憶T細胞。 取決於接種方法，獲得的記憶T淋巴細胞在血液和組織之間循環或存在於組織中並且不再循環。已知在組織中駐留的記憶T細胞在抗病毒再感染方麵的有效性，但是迄今為止它們抗腫瘤免疫的貢獻是未知的。

 

同時，研究的第一作者Michel Enamorado指出：“我們發現循環和組織駐留記憶細胞合作以產生最佳抗腫瘤免疫反應，組織駐留記憶細胞能夠產生重新循環記憶細胞的警戒狀態，導致更快更有效的免疫應答。

 

T淋巴細胞的過繼轉移

 

已經在患者中使用的另一種癌症免疫治療方法是靶向腫瘤T細胞的過繼轉移。作者表明過繼轉移的循環記憶T細胞能夠在感染癌症的背景下將自身轉化為常駐記憶細胞。此外，通過將這種轉移與目前用於受體PD-1抗體的T細胞抗腫瘤反應的臨床策略相結合，進一步提高了免疫治療效率。作者還發現，細胞毒性記憶T細胞抗腫瘤反應的再激活需要樹突狀細胞的DC1亞型。

 

研究表明，最佳的抗腫瘤免疫反應需要產生循環和組織駐留T細胞記憶。兩種記憶T細胞亞型可以用現有的免疫治療方法重新激活，二者的再激活都需要DC1樹突狀細胞。癌症免疫治療不僅僅是可以有效促進原發性腫瘤排斥的治療方法；而且，它也是手術後阻止原發性腫瘤轉移的基礎工具。

 

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