Inflammatory Conditions Dictate the Effect of Mesenchymal Stem Cells on B Cell Function

Abstract

: The immunomodulatory capacity of mesenchymal stem or stromal cells (MSC) makes them a promising therapeutic tool after solid organ transplantation. The effects of MSC on B cells in vitro are characterized by an abrogation of memory and plasmablast formation and induction of regulatory B cells. MSC infused in patients might encounter an inflammatory environment which could influence the immunomodulatory effect of MSC. Therefore, we investigated how MSC interact with B cells under inflammatory conditions. In the present study MSC were isolated from adipose tissue and pre-treated with 50 ng/ml IFN-γ for 96h (MSC-IFN-γ) to simulate inflammatory conditions. Mature B cells were obtained from spleens by CD43- selection. B cells were co-cultured with MSC at a 10:1 ratio and stimulated with anti-IgM, anti-CD40 and IL-2. B cell proliferation and phenotype were analyzed by flow cytometry, and IgG and IL-10 production quantified by ELISA. MSC were not capable of inhibiting the proliferation of B cells, while MSC-IFN-y significantly reduced B cell proliferation and were more potent in inhibiting IgG production by B cells. In contrast, MSC increased the percentage of IL-10 producing regulatory B cells (CD19+CD24hiCD38hi), whereas MSC-IFNy lacked this capacity. Culturing B cells with MSC-IFN-y in a transwell system in order to investigate the mechanisms of action abolished the effect on B cell proliferation. Indoleamine 2,3 dioxygenase (IDO) expression was highly induced in MSC-IFN-y, leading to degradation and depletion of tryptophan (TRP). By abolishing the effect of IDO by the addition of TRP to the co-culture, B cell proliferation and induction of regulatory B cells was restored. Immunological conditions dictate the effect of MSC on B cell function. under immunological quiescent conditions MSC stimulate regulatory B cell induction, whereas under inflammatory conditions MSC inhibit B cell proliferation and IgG production through depletion of TRP. This knowledge is useful for designing of MSC therapy for specific purposes by appropriate pre-treatment of MSC.