Journal
JOURNAL OF CLINICAL INVESTIGATION
Volume 128, Issue 10, Pages 4588-4603Publisher
AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/JCI121960
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Funding
- Roche/UCL Impact Studentship
- Medical Research Council [G0801213]
- Wellcome Trust Senior Investigator Award [101849/Z/13/A]
- Wellcome Trust [101849/Z/13/A] Funding Source: Wellcome Trust
- MRC [MR/R008698/1, G0801213] Funding Source: UKRI
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B cells are increasingly recognized as playing an important role in the ongoing control of hepatitis B virus (HBV). The development of antibodies against the viral surface antigen (HBV surface antigen [HBsAgs]) constitutes the hallmark of resolution of acute infection and is a therapeutic goal for functional cure of chronic HBV (CHB). We characterized B cells directly ex vivo from the blood and liver of patients with CHB to investigate constraints on their antiviral potential. Unexpectedly, we found that HBsAg-specific B cells persisted in the blood and liver of many patients with CHB and were enriched for T-bet, a signature of antiviral potential in B cells. However, purified, differentiated HBsAg-specific B cells from patients with CHB had defective antibody production, consistent with undetectable anti-HBs antibodies in vivo. HBsAg-specific and global B cells had an accumulation of CD21(-)CD27(-) atypical memory B cells (atMBC) with high expression of inhibitory receptors, including PD-1. These atMBC demonstrated altered signaling, homing, differentiation into antibody-producing cells, survival, and antiviral/proinflammatory cytokine production that could be partially rescued by PD-1 blockade. Analysis of B cells within healthy and HBV-infected livers implicated the combination of this tolerogenic niche and HBV infection in driving PD-1(hi) atMBC and impairing B cell immunity.
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