Immunomodulatory mechanisms of mesenchymal stem cells and their therapeutic applications.

In the recent years, many studies have shown that MSCs must be stimulated by pro-inflammatory cytokines or other immune mediators before they can modulate immune cells in inflamed and damaged tissues. MSCs appear to be involved in inducing several regulatory immune cells, such as Tregs, Bregs, and regulatory NK cells. This new immune milieu created by MSCs may establish a tolerogenic environment that leads to an optimal condition for the treatment of immune diseases. The mechanisms of MSC action to treat immune disorders need to be further investigated in more detail. Since there have been some contradictory outcomes of clinical trials, it is necessary to perform large-scale and randomized clinical studies, such as a phase 3 placebo-controlled double-blind study of a third party MSCs to optimize MSC administration and to prove safety and efficacy of MSC treatment. MSCs offer great therapeutic promise, especially for the treatment of difficult-to-treat immune diseases.

Peripheral 4-1BB signaling negatively regulates NK cell development through IFN-gamma.

Stimulation of 4-1BB (CD137) was shown to produce strong anticancer effects in vivo. In contrast, 4-1BB-deficient (4-1BB(-/-)) B6 mice are remarkably resistant to tumor growth. We set out to determine the mechanisms involved in these seemingly contradictory observations. We found that the therapeutic effects of 4-1BB triggering were mainly dependent on CD8(+) T cells and partially on NK cells, whereas CD8(+) T and NK cells were equally needed to suppress tumor growth in 4-1BB(-/-) mice. Cellular analysis showed that the frequency and number of NK cells in the spleen and bone marrow were decreased by 4-1BB triggering but were increased in the absence of 4-1BB signaling in tumor-challenged mice. The 4-1BB-mediated downregulation of NK cell development was primarily dependent on IFN-gamma, which was produced by peripheral CD8(+) T and NK cells. The suppression of NK cell development by 4-1BB-mediated IFN-gamma production occurred in the bone marrow. As 4-1BB signaling increased in the periphery, more CD8(+) T cells but fewer NK cells contributed to the antitumor immunity. As 4-1BB signaling decreased, more NK cells participated in the antitumor immunity. We conclude that 4-1BB signaling results in a shift of the dominant type of immune cell in antitumor immunity from the innate NK cell to the adaptive CD8(+) T cell and that the level of IFN-gamma is critical for this 4-1BB-mediated shift.