Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C
Tina Senff, … , Georg M. Lauer, Jörg Timm
Tina Senff, … , Georg M. Lauer, Jörg Timm
Published December 14, 2021
Citation Information: JCI Insight. 2022;7(2):e155432. https://doi.org/10.1172/jci.insight.155432.
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Research Article Immunology Virology

Peripheral blood iNKT cell activation correlates with liver damage during acute hepatitis C

Abstract

Invariant NK T (iNKT) cells are implicated in viral clearance; however, their role in hepatitis C virus (HCV) infection remains controversial. Here, iNKT cells were studied during different stages of HCV infection. iNKT cells from patients with acute HCV infection and people who inject drugs (PWID) with chronic or spontaneously resolved HCV infection were characterized by flow cytometry. In a longitudinal analysis during acute HCV infection, frequencies of activated CD38+ iNKT cells reproducibly declined in spontaneously resolving patients, whereas they were persistently elevated in patients progressing to chronic infection. During the first year of infection, the frequency of activated CD38+ or CD69+ iNKT cells strongly correlated with alanine transaminase levels with particularly pronounced correlations in spontaneously resolving patients. Increased frequencies of activated iNKT cells in chronic HCV infection were confirmed in cross-sectional analyses of PWID with chronic or spontaneously resolved HCV infection; however, no apparent functional differences were observed with various stimulation protocols. Our data suggest that iNKT cells are activated during acute hepatitis C and that activation is sustained in chronic infection. The correlation between the frequency of activated iNKT cells and alanine transaminase may point toward a role of iNKT cells in liver damage.

Authors

Tina Senff, Christopher Menne, Christine Cosmovici, Lia Laura Lewis-Ximenez, Jasneet Aneja, Ruth Broering, Arthur Y. Kim, Astrid M. Westendorf, Ulf Dittmer, Norbert Scherbaum, Georg M. Lauer, Jörg Timm

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Figure 4

iNKT cell function does not differ between HCV RNA–positive and HCV RNA–negative PWID.

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iNKT cell function does not differ between HCV RNA–positive and HCV RNA–...
(A) PBMCs from HCV RNA–positive (n = 13) and HCV RNA–negative (n = 13) donors were stimulated in vitro for 10 days with α-galactosylceramide (αGalCer) and IL-2, and fold change of invariant NK T (iNKT) cell frequency was analyzed. Groups were compared by Mann-Whitney U test. (B) Frequency of CD38+ and CD127+ iNKT cells in HCV RNA–positive and –negative patients ex vivo and after 10 days of in vitro expansion with αGalCer and IL-2 (1-way ANOVA, **P ≤ 0.01, ***P ≤ 0.001). (C and D) PBMCs from HCV RNA–positive (n = 13) and HCV RNA–negative (n = 13) donors were stimulated in vitro with phorbol myristate acetate (PMA) and ionomycin for 5 hours in presence of brefeldin A (BFA) for the last 4 hours ex vivo (C) or after 10 days (D) of expansion with αGalCer and IL-2. Intracellular cytokine staining was performed for IFN-γ and IL-2 and degranulation was analyzed by staining of CD107a. (E) PBMCs from healthy donors were stimulated with PMA and ionomycin; αGalCer; a cocktail of IL-12, IL-15, and IL-18; or a combination of αGalCer, IL-12, IL-15, and IL-18 for 24 hours, and IFN-γ secretion was analyzed by intracellular cytokine staining (ICS). (F) PBMCs from HCV RNA–positive (n = 9) and HCV RNA–negative (n = 8) donors were stimulated with a combination of αGalCer and IL-12, IL-15, and IL-18 for 24 hours, with addition of BFA for the last 4 hours, and IFN-γ secretion was analyzed by ICS. Groups were compared by unpaired t test. In box plots, horizontal bars indicate the medians, boxes indicate 25th to 75th percentiles, and whiskers indicate 10th and 90th percentiles.