Abstract
Circulating T follicular helper (cTfh) cells have been identified as counterparts of germinal center Tfh (GC Tfh) cells in humans and can support T-dependent B cell maturation and antibody production in vitro. However, the role of cTfh cells in neutralizing antibody (nAb) responses in HCV infection remains unclear. Here, we characterized the phenotype and function of cTfh cells and demonstrated the associations of cTfh cells and their subsets with nAb responses in HCV infection. A total of 38 HCV-infected individuals and 28 healthy controls were enrolled from a pool of injection drug users. The frequency and function of blood Tfh cells were analyzed by flow cytometry. The titers and breadths of serum nAbs were measured using HCV pseudo-particle neutralization assays. Herein, we report several key observations. First, HCV infection skewed cTfh toward CXCR3+ cTfh cell differentiation. Second, the frequency of CXCR3+ cTfh cells positively correlated with HCV nAb titers and breadths. Third, CXCR3+ cTfh cells showed higher expression of Tfh-associated molecules (PD-1, ICOS, IL-21, Bcl-6) compared with CXCR3− cTfh cells from individuals with HCV infection. Coculture of cTfh cells and autologous memory B cells in vitro indicated that CXCR3+ cTfh cells show a superior ability to support HCV E2-specific B cell expansion compared with CXCR3− cTfh cells from individuals with HCV infection. HCV infection skews cTfh cells toward CXCR3-biased Tfh cell differentiation, which positively correlates with the magnitude and breadth of the HCV nAb response. It is our hope that these findings will provide insights for the rational design of a nAb-based HCV vaccine.
Highlights
Neutralizing antibodies play an important role during HCV infection, as a robust early induction of appropriate neutralizing antibody (nAb) levels in acute infection contributes to spontaneous HCV clearance and to the prevention of reinfection[1,2,3]
We show that HCV infection skewed Circulating T follicular helper (cTfh) cells toward CXCR3-biased T follicular helper (Tfh) cell differentiation, which positively correlated with the magnitude and breadth of the HCV nAb response
These results suggested that HCV infection promoted cTfh cell expansion and skewed cTfh cells toward CXCR3+ cTfh cell differentiation, which is consistent with a report showing that most antigen-specific CD4+ T cells express CXCR3 and exhibit similar properties to Tfh cells in acute HCV infection, based on MHC II tetramer staining[23]
Summary
Neutralizing antibodies (nAbs) play an important role during HCV infection, as a robust early induction of appropriate nAb levels in acute infection contributes to spontaneous HCV clearance and to the prevention of reinfection[1,2,3]. T follicular helper (Tfh) cells are a CD4+ T cell subset specialized to regulate the types of antibody production that occur in the germinal center (GC)[7,8] These cells, which reside in the GC, exhibit a CXCR5+ PD-1hi ICOShi surface phenotype and express high levels of the master transcription factor Bcl-6 to regulate the differentiation of antigen-specific memory B cells and plasma cells by secreting the cytokine IL-219–13. Accumulating evidence has shown that human blood CXCR3− cTfh (including Tfh[2] and Tfh17) cells are major functional counterparts of GC Tfh cells that efficiently induce naïve B cells to produce antibodies in vitro, whereas CXCR3+ cTfh cells lack these properties[14,15,16] Consistent with these findings, Locci M. et al reported that circulating PD-1+ CXCR3− CXCR5+ memory Tfh cells are highly functional and correlate with a broad neutralizing HIV antibody www.nature.com/scientificreports/. It is our hope that these findings will provide clues for the rational design of an HCV vaccine
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