According to Hepatitis C Virus (HCV) Infection Stage, Interleukin-7 Plus 4-1BB Triggering Alone or Combined with PD-1 Blockade Increases TRAF1
low
HCV-Specific CD8
+
Cell Reactivity
Authors: Moreno-Cubero Elia , Subirá Dolores , Sanz-de-Villalobos Eduardo , Parra-Cid Trinidad , Madejón Antonio , Miquel Joaquín , Olveira Antonio , González-Praetorius Alejandro , García-Samaniego Javier , Larrubia Juan-Ramón 
Published: November 2017

Hepatitis C virus (HCV)-specific CD8
+
T cells suffer a progressive exhaustion during persistent infection (PI) with HCV. 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-positive [pentamer
+
]/CD8
+
T cells) from patients with PI and resolved infection (RI) after treatment were studied. The duration of HCV infection and the liver fibrosis progression rate inversely correlated with the likelihood of detection of 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/midduration PI was characterized by detectable peripheral PD-1
+
CD127
low
TRAF1
low
cells. After triggering of T cell receptors (TCR), the TRAF1 level positively correlated with the levels of CD127, Mcl-1, and CD107a expression and proliferation intensity but negatively with PD-1 expression, linking TRAF1
low
to exhaustion.
In vitro
treatment with interleukin-7 (IL-7) upregulated TRAF1 expression, while treatment with transforming growth factor-β1 (TGF-β1) did the opposite, suggesting that the IL-7/TGF-β1 balance, besides TCR stimulation, could be involved in TRAF1 regulation. In fact, the serum TGF-β1 concentration was higher in patients with PI than in patients with RI, and it negatively correlated with TRAF1 expression. In line with IL-7 increasing the level of TRAF1 expression, IL-7 plus 4-1BBL treatment
in vitro
enhanced T cell reactivity in patients with short/midduration infection. However, in patients with long-lasting PI, anti-PD-L1, in addition to the combination of IL-7 and 4-1BBL, was necessary to reestablish T cell proliferation in individuals with slowly progressing liver fibrosis (slow fibrosers) but had no effect in rapid fibrosers. In conclusion, a peripheral hyporeactive TRAF1
low
HCV-specific CD8
+
T cell response, restorable by IL-7 plus 4-1BBL treatment, characterizes short/midduration PI. In long-lasting disease, HCV-specific CD8
+
T cells are rarely detectable
ex vivo
, but treatment with IL-7, 4-1BBL, and anti-PD-L1 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 the failure of costimulation. This study describes exhausted specific T cells, characterized by low levels of expression of the signal transducer TRAF1 of the positive costimulatory pathway 4-1BB/4-1BBL. IL-7 upregulated TRAF1 expression and improved T cell reactivity in patients with short/midduration disease, while in patients with long-lasting infection, it was also necessary to block the negative PD-1/PD-L1 checkpoint. When the results are taken together, this work supports novel ways of restoring the specific CD8
+
T cell response, shedding light on the importance of TRAF1 signaling. This could be a promising target for future immunotherapy.