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

• Published in: The Journal of clinical investigation Vol. 128; no. 10; pp. 4573 - 4587
• Main Authors: Salimzadeh, Loghman, Le Bert, Nina, Dutertre, Charles-A., Gill, Upkar S., Newell, Evan W., Frey, Christian, Hung, Magdeleine, Novikov, Nikolai, Fletcher, Simon, Kennedy, Patrick T.F., Bertoletti, Antonio
• Format: Journal Article
• Language: English
• Published: United States American Society for Clinical Investigation 01.10.2018
• Subjects: Adult; B-Lymphocytes - immunology; B-Lymphocytes - pathology; Care and treatment; CD40 Ligand - immunology; Cellular proteins; Development and progression; Female; Genetic aspects; Health aspects; Hepatitis B; Hepatitis B surface antigen; Hepatitis B Surface Antigens - immunology; Hepatitis B, Chronic - immunology; Hepatitis B, Chronic - pathology; Hepatitis B, Chronic - therapy; Humans; Immune response; Immunity, Humoral; Interleukin-2 - immunology; Interleukin-21; Interleukins - immunology; Male; Programmed Cell Death 1 Receptor - antagonists & inhibitors; Programmed Cell Death 1 Receptor - immunology; Hepatitis; Infectious disease; B cells; Hepatology
• ISSN: 0021-9738; 1558-8238; 1558-8238
• DOI: 10.1172/JCI121957

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.