IL-10–Producing Regulatory B Cells in the Pathogenesis of Chronic Hepatitis B Virus Infection

Abstract

A regulatory subset of B cells has been found to modulate immune responses in autoimmunity, infection and cancer but has not been investigated in the setting of human persistent viral infection. IL-10 is elevated in patients with chronic hepatitis B virus infection (CHB)3 but its cellular sources and impact on antiviral T cells have not been addressed. We investigated the role of IL-10 and regulatory B cells in the pathogenesis of CHB. Serum IL-10 levels were studied longitudinally in patients with CHB undergoing spontaneous disease flares. There was a close temporal correlation between IL-10 levels and fluctuations in viral load or liver inflammation. Blockade of IL-10 in vitro rescued polyfunctional virus-specific CD8 T cell responses. To investigate the potential contribution of regulatory B cells, their frequency was measured directly ex vivo and after exposure to stimuli relevant to HBV (CpG or HBV antigens). IL-10-producing B cells were enriched in patients, and their frequency correlated temporally with hepatic flares, both after stimulation and directly ex vivo. Phenotypically, these cells were predominantly immature (CD19+CD24hiCD38hi) ex vivo; sorted CD19+CD24hiCD38hi cells suppressed HBV-specific CD8 T cell responses in an IL-10-dependent manner. In summary, these data reveal a novel IL-10-producing subset of B cells able to regulate T cell immunity in CHB.

Immune Regulation and Evasion of Mammalian Host Cell Immunity During Viral Infection

“…In case of chronic hepatitis B virus infection, immunosuppressive regulatory B cells (Bregs) have been recently reported. Those Bregs are found to regulate anti-viral CTL response in an IL-10-dependent manner [30].…”

Bregs in Chronic HBV: Is It Time for Bragging Rights?

“…regulatory T (Treg) cells exert multiple, negative regulatory functions on the effector immune cells, contributing substantially to the impairment of HBV clearance. Recently, a new family of regulatory cells, regulatory B cells (Bregs), was reported to control immune responses at the innate and the adaptive levels [2], and only few studies, including the present paper, have investigated the role of Breg cells in chronic hepatitis B (CHB) [3,4]. B lymphocytes were initially identified for their production of cell surface antibody and their subsequent differentiation into plasma cells and consequent antibody secretion, with their antigen-presenting function later identified.…”

“…Similar to Tregs, Bregs exert their suppressive properties through several mechanisms: Th1 and Th17 differentiation inhibition, Treg induction, and also through a direct inhibitory effect on antigen presentation by dendritic cells [3,4,[13][14][15]. Breg subtypes may be homologous to Treg subtypes (''Br1'' cells expressing IL-10, ''Br3'' cells expressing TGF-b), although the Br1 subtype seems to predominate.…”

“…A pioneering study performed by Das et al [3] reported increased Breg cells in the peripheral blood of patients with CHB who underwent spontaneous hepatic flare, demonstrating suppressive IL-10 mediated activity of Breg on HBV-specific CD8 cells in vitro. Interestingly, Breg temporally associated with the spontaneous flare, reflected by increased viral load and liver inflammation.…”

“…Since B cells and T cells have the potential to infiltrate the liver [3,17], they are possible therapeutic targets in the immunological control of liver inflammation. In the setting of chronic persistent hepatitis B virus infection, Breg and Treg are upregulated, suppressing persistent inefficient effector T cell response in the liver.…”