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, Bert, Nina Le, 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: Ann Arbor American Society for Clinical Investigation 01.10.2018
• Subjects: Antigens; Biomedical research; CD40L protein; Chronic infection; Cytokines; Fluorophores; Gastroenterology; Genotype & phenotype; Heparan sulfate; Hepatitis; Hepatitis B; Hepatitis B surface antigen; Hepatology; Humoral immunity; Infections; Interleukin 2; Interleukin 21; Lymphocyte receptors; Lymphocytes; Lymphocytes B; Lymphocytes T; Maturation; PD-1 protein; Phenotypes; Surface antigens; T cell receptors; Vaccination; Vaccines
• DOI: 10.1172/JCI121957.
• ISSN: 0021-9738

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 (CD21'°) 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.