title: CD4+ CXCR5+ T cells in chronic HCV infection produce less IL-21, yet are efficient at supporting B cell responses.
abstract: OBJECTIVE
  During chronic HCV infection, T cell dependent virus-specific antibodies are produced. However, the role of B-T cell interaction in chronic HCV is largely unknown. CD4(+)CXCR5(+) T follicular helper (TFH)-cells activate B cells and are important for clearance of various chronic viral infections. We investigated the function of TFH cells and B cells in liver and in peripheral blood of chronic HCV patients.
  
  
  METHODS
  T cells from chronic HCV patients and healthy individuals were analysed for expression of CXCR5, PD-1, ICOS, and IL-21 and IFN-γ production by flow cytometry. CD19(+) B cell subpopulations were identified on the basis of CD27 and IgD expression. In order to assess the frequency and function of T cells and B cells in liver follicles, immunohistochemistry was performed for CD3, CXCR5, Bcl6, IL-21, CD20, IgD, IgM, and IgG.
  
  
  RESULTS
  The frequency of IL-21-producing CXCR5(+)CD4(+) T cells in blood was lower in HCV patients compared to healthy individuals (p=0.002), which was reflected by lower serum IL-21 levels (p<0.001). Nonetheless, CXCR5(+)CD4(+) T cells from HCV patients and healthy individuals were equally capable to stimulate CD19(+)CD27(+) memory B cells into IgG and IgM-producing plasmablasts. Importantly, human intrahepatic TFH cells and their related function were identified by immunohistochemistry on liver biopsies for CD3, Bcl6, and CD20 within portal areas and follicles.
  
  
  CONCLUSIONS
  The specific localization of TFH cells and IgG and IgD/IgM-producing B cells suggests a functional B-T cell environment in liver follicles during HCV infection. The decreased frequency of IL-21-producing CXCR5(+)CD4(+) T cells and lower serum IL-21 levels in chronic HCV patients did not lead to an altered TFH-B cell interaction.
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Michelle
authors.initials: M
authors.lastname: Spaan
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Kim
authors.initials: K
authors.lastname: Kreefft
authors.affiliation: Department of Internal Medicine, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Gretchen N
authors.initials: GN
authors.lastname: de Graav
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Willem P
authors.initials: WP
authors.lastname: Brouwer
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: de Knegt
authors.affiliation: Department of Pathology, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Fibo J W
authors.initials: FJ
authors.lastname: ten Kate
authors.affiliation: Department of Internal Medicine, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Carla C
authors.initials: CC
authors.lastname: Baan
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, The Netherlands.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vanwolleghem
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, The Netherlands; Liver Clinic University Health Network, Division of Gastroenterology, University of Toronto, Canada.
authors.forename: Harry L A
authors.initials: HL
authors.lastname: Janssen
authors.affiliation: Department of Gastroenterology and Hepatology, Erasmus MC - University Medical Center Rotterdam, The Netherlands. Electronic address: p.a.boonstra@erasmusmc.nl.
authors.forename: Andre
authors.initials: A
authors.lastname: Boonstra
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D019698:Hepatitis C, Chronic / Q000276:immunology* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007111:Immunity, Cellular; D007378:Interleukins / Q000096:biosynthesis*; D008297:Male; D008875:Middle Aged; D054380:Receptors, CXCR5 / Q000276:immunology* / Q000378:metabolism; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology* / Q000378:metabolism; D000098546:Interleukin-21
chemical_list: C095085:CXCR5 protein, human; D007378:Interleukins; D054380:Receptors, CXCR5; D000098546:Interleukin-21
keywords: Chronic hepatitis C; IL-21; Immunology; Intra-hepatic; T follicular helper cells