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PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection
Loghman Salimzadeh, … , Patrick T.F. Kennedy, Antonio Bertoletti
Loghman Salimzadeh, … , Patrick T.F. Kennedy, Antonio Bertoletti
Published August 7, 2018
Citation Information: J Clin Invest. 2018;128(10):4573-4587. https://doi.org/10.1172/JCI121957.
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Research Article Hepatology Infectious disease

PD-1 blockade partially recovers dysfunctional virus–specific B cells in chronic hepatitis B infection

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Abstract

Chronic HBV (CHB) infection suppresses virus-specific T cells, but its impact on humoral immunity has been poorly analyzed. Here, we developed a dual-staining method that utilizes hepatitis B virus (HBV) surface antigens (HBsAg) labeled with fluorochromes as “baits” for specific ex vivo detection of HBsAg-specific B cells and analysis of their quantity, function, and phenotype. We studied healthy vaccinated subjects (n = 18) and patients with resolved (n = 21), acute (n = 11), or chronic (n = 96) HBV infection and observed that frequencies of circulating HBsAg-specific B cells were independent of HBV infection status. In contrast, the presence of serum HBsAg affected function and phenotype of HBsAg-specific B cells that were unable to mature in vitro into Ab-secreting cells and displayed an increased expression of markers linked to hyperactivation (CD21lo) and exhaustion (PD-1). Importantly, B cell alterations were not limited to HBsAg-specific B cells, but affected the global B cell population. HBsAg-specific B cell maturation could be partially restored by a method involving the combination of the cytokines IL-2 and IL-21 and CD40L-expressing feeder cells and was further boosted by the addition of anti–PD-1 Abs. In conclusion, HBV infection has a marked impact on global and HBV-specific humoral immunity, yet HBsAg-specific B cells are amenable to a partial rescue by B cell–maturing cytokines and PD-1 blockade.

Authors

Loghman Salimzadeh, Nina Le Bert, Charles-A. Dutertre, Upkar S. Gill, Evan W. Newell, Christian Frey, Magdeleine Hung, Nikolai Novikov, Simon Fletcher, Patrick T.F. Kennedy, Antonio Bertoletti

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Figure 8

PD-1 blockage partially recovers dysfunctional HBsAg-specific B cells of CHB patients.

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PD-1 blockage partially recovers dysfunctional HBsAg-specific B cells of...
(A) mRNA expression of PD-1 in the indicated B cell subsets of 5 CHB patients measured by NanoString. (B) Surface PD-1 expression on the B cell subsets of 96 CHB patients measured by flow cytometry. (C) Flow cytometric data of MBCs from 141 samples analyzed by UMAP and concatenated. Four subsets of MBCs were delineated (left, plots reshown from Figure 6A), and PD-1+ MBCs are shown (right). (D) MBCs of 15 healthy vaccinated (left) and 76 CHB patients (right) were downsampled to equal cell numbers. Density UMAP plots are shown; the cluster of AtM B cells is highlighted in red. Right bar graph shows percentage of global MBCs with an AtM phenotype in 17 healthy vaccinated and 96 CHB patients. (E) Double-positive HBsAg-D550+D650+ B cells from 15 healthy vaccinated (left) and 76 CHB patients (right) were concatenated, downsampled to normalized frequencies, and overlaid onto the UMAP plot of global concatenated MBCs; the cluster of AtM B cells is highlighted in red. Right bar graph shows percentage of HBsAg-specific B cells with an AtM phenotype in healthy vaccinated and CHB patients. (F) MFI of PD-1 on global MBCs and HBsAg-specific MBCs of 96 CHB patients. (G) Double-positive HBsAg-D550+D650+ MBCs from 4 CHB patients and 3 healthy vaccinated subjects were FACS sorted and cocultured for 13 days with CD40L-expressing feeder cells in the presence of IL-2 and IL-21, with or without anti–PD-1 Ab (schematic at left). Subsequently, anti-HBs–secreting cells were detected by ELISpot assay (right). Average fold changes in the number of anti-HBs spots are shown above the plots. Data are presented as median, and statistical analysis was performed by the Mann-Whitney U test (D and E) and Wilcoxon’s paired t test (F and G). *P < 0.05; **P < 0.01; ****P < 0.0001.
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