Abstract
BackgroundThe increased activity of regulatory B cells (Breg) is known to be involved in immunosuppression during helminth infection, which is characterized by inducing IL-10-producing Breg cells. However, the current knowledge of B cell subsets differentiation and IL-10-independent immunoregulatory mechanisms of B cells in schistosomiasis is insufficient.MethodsBALB/c mice were percutaneously infected with cercariae for investigating the profile of B cell subsets during Schistosoma japonicum infection. B cells isolated from the spleen or peritoneal cavity were analyzed for the regulatory phenotype after stimulation with soluble egg antigens (SEA) in vitro. CD4+ T cells were then cocultured with B cells pretreated with or without anti-PD-L1 antibody for investigating the role of B cells from infected mice on regulating CD4+ T cells. Furthermore, the in vivo administration of anti-PD-L1 antibody was conducted to investigate the role of PD-L1 in regulating host immunity during infection.ResultsThe percentages of peritoneal and splenic B-1a cells, as well as marginal zone B (MZB) cells were decreased at eight and twelve weeks after infection compared to those from uninfected mice. In splenic B cells, TGF-β expression was increased at eight weeks but declined at twelve weeks of infection, and PD-L1 expression was elevated at both eight and twelve weeks of infection. In addition, SEA stimulation in vitro significantly promoted the expression of IL-10 in peritoneal B cells and CD5 in splenic B cells, and the SEA-stimulated splenic and peritoneal B cells preferentially expressed PD-L1 and TGF-β. The splenic B cells from infected mice were able to suppress the function of Th1 and Th2 cells in vitro but to expand the expression of Tfh transcription factor Bcl6, which was further enhanced by blocking PD-L1 of B cells before co-cultivation. Moreover, Th2 response and Bcl6 expression in CD4+ T cells were also increased in vivo by blocking PD-L1 after infection, although the hepatic pathology was slightly influenced.ConclusionsOur findings revealed that S. japonicum infection modulates the differentiation of B cell subsets that have the capability to affect the CD4+ T cell response. This study contributes to a better understanding of B cells immune response during schistosomiasis.
Highlights
The increased activity of regulatory B cells (Breg) is known to be involved in immunosuppression during helminth infection, which is characterized by inducing IL-10-producing Breg cells
Schistosoma japonicum infection modulates B cell differentiation We first investigated the B cell subsets in the peritoneal cavity (PerC) and spleen that have been confirmed to play a regulatory role in mice, such as B-1a cells, marginal zone B (MZB) cells and transitional 2 marginal zone B precursor (T2-MZP) cells, at different time points after S. japonicum infection (Fig. 1a, b)
Since B cells are crucial in egg-induced granulomatous response during schistosomiasis [6], our findings suggest that the immunoregulatory mechanism of B cells in S. japonicum-infected mice might be different from that in S. mansoni infections, the change of hepatic fibrosis led by B celldepletion in S. mansoni-infected mice was similar to that in mice infected with S. japonicum [30]
Summary
The increased activity of regulatory B cells (Breg) is known to be involved in immunosuppression during helminth infection, which is characterized by inducing IL-10-producing Breg cells. Chronic schistosome infection is characterized by the downregulation of the immune system, which is widely considered to be associated with a decreased prevalence of inflammatory diseases in their hosts [2, 3]. Most experimental studies on schistosome-induced regulatory B cells have focused on Schistosoma mansoni [4, 5]. Breg cells characterized by elevated PD-L1 suppress autoimmune disease and anti-tumor immune response through inhibiting antibody production and T cells activation [14,15,16,17]. A previous study has shown that through increasing the PD-L1 expression of macrophages, schistosome worms induce T cells anergy [19]
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