3 years ago

According to HCV infection stage, IL-7 plus 4-1BB triggering alone or combined with PD-1 blockade increases TRAF1(low) HCV-specific CD8(+) cell reactivity.

Antonio Madejón, Eduardo Sanz-de-Villalobos, Joaquín Miquel, Alejandro González-Praetorius, Trinidad Parra-Cid, Dolores Subirá, Javier García-Samaniego, Juan-Ramón Larrubia, Antonio Olveira, Elia Moreno-Cubero
Hepatitis C virus (HCV)-specific CD8(+) T cells suffer a progressive exhaustion during persistent HCV infection (PI). This process could involve the positive immune checkpoint 4-1BB/4-1BBL, through the loss of its signal transducer TRAF1. To address this issue, peripheral HCV-specific CD8(+) T cells (Pentamer(+)/CD8(+)) from patients with PI and resolved infection after treatment (RI) were studied. Duration of HCV infection and liver fibrosis progression rate inversely correlated with the likelihood of detecting peripheral pentamer(+)/CD8(+) cells. In PI, pentamer(+)/CD8(+) cells had impaired antigen-specific reactivity that worsened when these cells were not detectable ex-vivo Short/mid-lasting PI was characterized by detectable peripheral PD-1(+) CD127(low) TRAF1(low) cells. After TCR triggering, TRAF1 level positively correlated with CD127, Mcl-1, CD107a and proliferation intensity, but negatively with PD-1, linking TRAF1(low) to exhaustion. IL-7 in-vitro treatment up-regulated TRAF1, while TGF-β1 did the opposite, suggesting that IL-7/TGF-β1 balance, besides TCR stimulation, could be involved in TRAF1 regulation. In fact, TGF-β1 serum concentration was higher in PI than in RI patients, and it negatively correlated with TRAF1 expression. In line with IL-7 increasing TRAF1 level, IL-7/4-1BBL in-vitro treatment enhanced T cell reactivity in short/mid-lasting infection. However, in long-lasting PI, anti-PD-L1 in addition to IL-7/4-1BBL combination was necessary to re-establish T cell proliferation in slow fibrosers, but had no effect in rapid fibrosers. In conclusion, a peripheral hypo-reactive TRAF1(low) HCV-specific CD8(+) T cell response, restorable by IL-7/4-1BBL treatment, characterizes short/mid-length PI. In long-lasting disease, HCV-specific CD8(+) T cells are rarely detectable ex-vivo, but IL-7/4-1BBL/anti-PD-L1 treatment recovers their reactivity in-vitro in slow fibrosers.IMPORTANCE Hepatitis C virus (HCV) infects 71 million people worldwide. Two thirds develop a chronic disease that can lead to cirrhosis and hepatocellular carcinoma. Direct-acting antivirals clear the infection but there are still patients who relapse. In these cases, additional immunotherapy could play a vital role. A successful anti-HCV immune response depends on virus-specific CD8(+) T cells. During chronic infection, these cells are functionally impaired, which could be due to co-stimulation failure. This study describes exhausted specific T cells, characterized by low expression of the signal transducer TRAF1 of the positive co-stimulatory pathway 4-1BB/4-1BBL. IL-7 up-regulated TRAF1 and improved T cell reactivity in short/mid duration disease, while in long-lasting infection, it was also necessary to block the negative checkpoint PD-1/PD-L1. Taken together, this work supports novel ways of restoring specific CD8(+) T cell response, shedding light on the importance of TRAF1 signaling. This could be a promising target for future immunotherapy.

Publisher URL: http://doi.org/10.1128/JVI.01443-17

DOI: 10.1128/JVI.01443-17

You might also like
Discover & Discuss Important Research

Keeping up-to-date with research can feel impossible, with papers being published faster than you'll ever be able to read them. That's where Researcher comes in: we're simplifying discovery and making important discussions happen. With over 19,000 sources, including peer-reviewed journals, preprints, blogs, universities, podcasts and Live events across 10 research areas, you'll never miss what's important to you. It's like social media, but better. Oh, and we should mention - it's free.

  • Download from Google Play
  • Download from App Store
  • Download from AppInChina

Researcher displays publicly available abstracts and doesn’t host any full article content. If the content is open access, we will direct clicks from the abstracts to the publisher website and display the PDF copy on our platform. Clicks to view the full text will be directed to the publisher website, where only users with subscriptions or access through their institution are able to view the full article.