Bacterially activated B-cells drive T cell differentiation towards Tr1 through PD-1/PD-L1 expression

Regulatory B cells (Bregs) play a crucial role in immunological tolerance primarily through the production of IL-10 in many diseases including autoimmune disorders, allergy, infectious diseases, and cancer. To date, various Breg subsets with overlapping phenotypes have been identified. However, the roles of Bregs in Helicobacter infection are largely unknown. In the present study, we investigate the phenotype and function of Helicobacter - stimulated B cells. Our results demonstrate that Helicobacter fells - stimulated IL-10-producing B cells (Hf-stim-IL-10(+) B) are composed of B10 and Transitional 2 Marginal Zone Precursor (T2-MZP) cells with expression of CD9, Tim-1, and programmed death 1 (PD-1). On the other hand, Helicobacter fells-stimulated IL-10- non-producing B B (Hf-stim- IL-10(-) B) cells are mainly marginal zone (MZ) B cells that express PD-L1 and secrete TGF-beta, IL-6, and TNF-alpha, and IgM and IgG2b. Furthermore, we show that both Hf-stim-IL-10(+) B cells and Hf-stim-IL-10(-) B cells induce CD49b(+) LAG-3(+) Tr1 cells. Here, we describe a novel mechanism for PD-1/PD-L1- driven B cell-dependent Tr1 cell differentiation. Finally, we explore the capability of Hf-stim-IL-10(-) B cells to induce Th17 cell differentiation, which we find to be dependent on TGF-beta. Taken together, the current study demonstrates that Hf-stim- B cells induce Tr1 cells through the PD-1/PD-L1 axis and Th17 cells by secreting TGF-beta.