title: Hepatitis C viraemia reversibly maintains subset of antigen-specific T-bet+ tissue-like memory B cells.
abstract: Chronic antigen exposure and/or ageing increases the frequency of T-box expressed in T cells (T-bet)-expressing B-lymphocytes in mice. The frequency and significance of B-cell T-bet expression during chronic hepatitis C (HCV) infection in human subjects has never been described.
  
  
  
  Healthy controls, cirrhotic and noncirrhotic HCV-infected patients, and non-HCV patients with cirrhosis were recruited. Peripheral blood mononuclear cells were phenotyped for expression of T-bet and related markers by flow cytometry. In a subset of patients who underwent antiviral therapy and were cured of HCV infection (sustained virological response), the dynamics of T-bet expression in B cells was monitored. After cure, convalescent B cells were tested for T-bet expression after re-exposure to infected plasma or recombinant HCV proteins.
  
  
  
  Forty-nine patients including 11 healthy donors, 30 hepatitis C-infected individuals (nine with liver cancer, 13 with cirrhosis, eight without cirrhosis) and eight patients with cirrhosis due to non-HCV-related cause were recruited. We found that B cells in patients with chronic HCV exhibited increased frequency of T-bet+ B cells relative to noninfected individuals (median 11.5% v. 2.2%, P<.0001) but that there were no significant differences between noncirrhotic, cirrhotic and cancer-bearing infected individuals. T-Bet+B cells expressed higher levels of CD95, CXCR3, CD11c, CD267 and FcRL5 compared to T-bet-B cells and predominantly exhibit a tissue-like memory CD27-CD21-phenotype independent of HCV infection. T-bet+B cells in HCV-infected patients were more frequently class-switched IgD-IgG+(40.4% vs. 26.4%, P=.012). Resolution of HCV infection with direct-acting antiviral (DAA) therapy leads to a marked reduction in the frequency of T-bet+B cells (median 14.1% pretreatment v. 6.7% end of treatment v. 6.1% SVR12, P≤.01). Re-exposure of convalescent (cured) B cells to viremic plasma and recombinant HCV E2 protein led to re-expression of T-bet.
  
  
  
  Chronic antigenemia in chronic HCV infection induces and maintains an antigen-specific T-bet+B cell. These B cells share markers with tissue-like memory B cells. Antigen-driven T-bet expression may be a critical suppressor of B-cell activation in chronic HCV infection.
authors.affiliation: Medicine and Research Services, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.|Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: L-Y
authors.initials: LY
authors.lastname: Chang
authors.affiliation: Medicine and Research Services, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.|Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.affiliation: Medicine and Research Services, Corporal Michael J. Crescenz VA Medical Center, Philadelphia, PA, USA.|Division of Gastroenterology, Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Kaplan
mesh_terms: D000328:Adult; D000368:Aged; D016175:B-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology*; D005260:Female; D020869:Gene Expression Profiling; D019698:Hepatitis C, Chronic / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory; D016130:Immunophenotyping; D008297:Male; D008875:Middle Aged; D020825:T-Box Domain Proteins / Q000032:analysis*; D014766:Viremia / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor
keywords: B cell; FcRL5; T-bet; age-associated B cells (ABCs); cirrhosis; hepatitis C; humoral immunity