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P92 CD161+ γ-δ T cells: defining their role in patients with and without chronic hepatitis C
  1. N Rajoriya1,
  2. C Willberg1,
  3. B Seigal2,
  4. YuHoi Kang1,
  5. J Phillips-Hughes3,
  6. J Collier4,
  7. E Barnes1,
  8. R Thimme2,
  9. P Klenerman2
  1. 1Peter Medawar Building for Pathogen Research, Oxford University
  2. 2Department of Medicine, University of Freiburg
  3. 3Radiology Department, Churchill Hospital, Oxford
  4. 4Department of Gastroenterology, John Radcliffe Hospital, Oxford

Abstract

Introduction γ-δ T cells have been found in blood/liver of patients infected with hepatitis C (HCV). CD161+ is a C-type lectin found on the surface of T cells in humans. HCV specific T-cells have been found to express CD161 with enrichment within the liver. The role & function of CD161+ γ-δ cells has not been established in HCV.

Aim To explore the phenotype and function of CD161+ γ-δ T cells in humans, and to assess the impact on these cells of HCV infection.

Method Whole blood/Peripheral Blood Mononuclear cell (PBMC) antibody staining with subsequent flow cytometry was performed to assess phenotype. Function was examined by Intracellular Cytokine staining (ICS). Intrahepatic lymhocytes (IHLs) were isolated from patients having liver biopsies for clinical indications with paired blood samples. Cord blood samples were used after ethical approval gained and consent from mothers.

Results In healthy controls, the CD161 subset encompassed a mean of 82.1 (±12.8)% of γ-δ cells. The CD161 subset expressed more CXCR3/CCR6/IL-18R (p=0.03/0.01 and 0.03 respectively) than the CD161- subset. The CD161+ cells expressed significantly more If-y/TNF-α (p=0.001 respectively) than the negative subset, and more Granzyme A, B and K and perforin in keeping with a Th1 profile. 20% of γ-δ cells from cord blood samples expressed CD161, suggesting it is an innate feature but expanded throughout life. Whole blood γ-δ populations were significantly reduced in HCV compared to healthy donors (70% v 40%, p=0.0031), with the proportion of CD161+ γ-δ T-cells reduced in chronic HCV (82.1% vs 39%, p=0.006). The γ-δ cells in HCV expressed significantly more activation markers (CD38/CD69) and CXCR6 than in healthy controls irrespective of CD161 status. Of the CD161+ γ-δ cells, the predominant subset were Vδ2 in healthy controls blood however in HCV this was significantly reduced (p=0.0173) with the Vδ1 subset dominating. On isolation of IHLs (n=17: 8 HCV, 3 HBV and rest NAFLD/NASH), there was an enrichment of CD3+ γ-δ T-cells in liver tissue compared to blood irrespective of CD161 status. On sub-analysis there were no statistical differences between CD161 status of the γ-δ cell T-cells when comparing viral v non-viral aetiologies.

Conclusion Our data suggests that HCV infection does directly reduce the γ-δ T-cell population in peripheral blood: mainly the CD161 subset. The virus also causes a reversal in the CD161 γ-δ T-cell population from Vδ2 to Vδ1 in the periphery, however it appears the enrichment of γ-δ T cells to the liver is not specific to CD161+ cells or to HCV infection. The CD161 phenotype present at birth but expanded throughout life. The CD161 subset appears to display a more Th1 profile and unlike their CD8 CD161++ α-β counterparts, CD161 expression by γ-δ T-cells is not tightly linked to a Type-17 differentiation pathway.

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