AbstractBackgroundHuman bocaviruses (HBoVs) have been demonstrated in respiratory and gastrointestinal infections; however, the immune response to them has not been studied in detail. In this study, we investigated the B cell immune responses to HBoV1 and HBoV2, representing two different species of bocaviruses in humans.MethodsWe analyzed the effects of stimulations with HBoV1 and 2 virus‐like particles (VLPs) and of co‐stimulation with HBoV1‐rhinovirus (RV) on cells of the immune system by flow cytometry, transcriptomics, and luminometric immune assays.ResultsHuman B cells, and particularly B regulatory cells (Breg cells), showed an increased immune response to HBoV1‐VLPs stimulation. These immune responses were also supported by increased IL‐1RA and PDL1 expressions in IL‐10⁺ B cells from peripheral blood mononuclear cells (PBMCs) stimulated with HBoV1‐VLPs. In addition, increased levels of IL‐10 and IL‐1RA were determined in the supernatants of PBMCs following HBoV1‐VLPs stimulation. HBoV1‐VLPs and RV co‐stimulation increased the IL‐10⁺ B cell population. Transcriptome analysis by next‐generation RNA sequencing showed an increased expression of IL‐10 signalling and Breg cell markers in PBMCs stimulated with HBoV1‐VLPs. Furthermore, TGF‐β and chemoattractants MIP‐1α, MIP‐1β and IP10 protein levels were high in the supernatants of PBMCs stimulated with HBoV1‐VLPs.ConclusionsThe findings demonstrate that in Breg cells, IL‐10 signalling pathways, and anti‐inflammatory activity are induced by HBoV1, which can explain the often mild nature of the disease. In addition, the immune regulatory response induced by HBoV1‐VLPs may indicate a potential immunomodulatory role of HBoV1 on the immune system and may represent an immune regulatory strategy.