TIM3-mediated differentiation of IL-10-producing CD25+ B cells by expanded regulatory T cells

Cell-based immunotherapy utilizing regulatory T cells (Tregs) has recently advanced into clinical applications, demonstrating promising results in phase I/II trials to prevent transplant rejection and treat autoimmune diseases. We have completed a clinical trial in renal transplant patients in which the significant biological effect was the increase of B cells with a regulatory phenotype in the blood of kidney transplant patients. The mechanisms by which Tregs regulate B cells and the specific molecules involved in this process remained poorly understood. In this study, we employed an in vitro system of co-culture of peripherally purified B cells and expanded Tregs to show that Tregs can induce a population of memory B cells that express IL-10 and CD25. This subset of B cells has been previously identified as one of humans' regulatory B cell populations. Notably, these expanded Tregs' regulation of B cells was found to be independent of IL-10 and reliant on direct cell contact. We established that TIM3 expression by Tregs was crucial for the induction of IL-10-producing CD25⁺ memory B cells. Our findings suggest that TIM3 is a critical molecule for the induction of regulatory B cells by Tregs, indicating that TIM3 expression by adoptively transferred Tregs is vital in diseases where B cells play a pathogenic role. KEY MESSAGES: Expanded Tregs induce IL-10+ CD25+ B cells. TIM3 expression on Tregs is crucial for IL-10+ B cell induction. Tregs require direct cell contact to regulate B cells. Blocking TIM3 reduces IL-10+ B cells but increases IFN-γ, TNF-α, IL-17. Tregs enhance regulatory B cell differentiation, promoting tolerance.