In vitro study of the mechanisms involved in the mesenchymal stromal cell (MSC) modulatory effect on B-cell functions

Accumulating evidence has suggested that human MSC are potent modulators of T cell activation and proliferation, mainly through the production of poorly defined soluble factors including the tryptophan-degrading enzyme IDO, a key immunosuppressive effector pathway whose expression on MSC is induced by IFN-γ. Although the research on MSC has mainly focused on their inhibitory role on T cells, it has been documented that MSC, under particular circumstances, significantly impair virtually all cells of the immune system, including B cells. However, regarding MSC immunomodulatory action on B cells, current literature is still poor and controversial, with few studies showing inconsistency in approaches and results. Basically, the influence of MSC on B cells seems different, probably depending on the microenvironment in which this interaction takes place. This study aimed at investigating the nature of the mechanisms by which MSC exert their immunomodulatory activity on B cells, either at resting conditions or following inflammatory priming. Our results confirm that MSC are not intrinsically capable of suppressing B cell proliferation, but require inflammatory stimuli to acquire B cell inhibitory potential. Inflammatory-primed MSC affect significantly B cell growth by inhibiting proliferation of activated B cells, in a manner that is independent of cell contact with B cells. Therefore, secretion of soluble factors plays a major role in MSC immunosuppression of B cells, being sufficient to provide maximal inhibition of B cell proliferation. We provide further evidence that B cell inhibition by MSC is not related to induction of B cell apoptosis or to early signaling events necessary for B cell activation. Conversely, as B cell inhibition is mainly induced by IFN-γ-primed MSC, it is reasonable that IFN-γ triggers IDO pathway in MSC, which in turn impairs B cell proliferation by interfering with the tryptophan metabolism. Overall, we provide further evidence about the mechanisms involved in the interaction between B cells and MSC at different functional states. Aspects concerning the role of IDO in B cell regulation need further investigation, and may be fundamental to develop new therapeutic approaches.