The Role of Mouse Mesenchymal Stem Cells in Differentiation of Naive T-Cells into Anti-Inflammatory Regulatory T-Cell or Proinflammatory Helper T-Cell 17 Population

Bone marrow-derived mesenchymal stem cells (MSCs) modulate immune response and can produce significant levels of transforming growth factor-beta (TGF-beta) and interleukin-6 (IL-6). These 2 cytokines represent the key factors that reciprocally regulate the development and polarization of naive T-cells into regulatory T-cell (Treg) population or proinflammatory T helper 17 (Th17) cells. In the present study we demonstrate that MSCs and their products effectively regulate expression of transcription factors Foxp3 and ROR gamma t and control the development of Tregs and Th17 cells in a population of alloantigen-activated mouse spleen cells or purified CD4(+) CD25(-) T-cells. The immunomodulatory effects of MSCs were more pronounced when these cells were stimulated to secrete TGF-beta alone or TGF-beta together with IL-6. Unstimulated MSCs produce TGF-beta, but not IL-6, and the production of TGF-beta can be further enhanced by the anti-inflammatory cytokines IL-10 or TGF-beta. In the presence of proinflammatory cytokines, MSCs secrete significant levels of IL-6, in addition to a spontaneous production of TGF-beta. MSCs producing TGF-beta induced preferentially expression of Foxp3 and activation of Tregs, whereas MSC supernatants containing TGF-beta together with IL-6 supported RORgt expression and development of Th17 cells. The effects of MSC supernatants were blocked by the inclusion of neutralization monoclonal antibody anti-TGF-beta or anti-IL-6 into the culture system. The results showed that MSCs represent important players that reciprocally regulate the development and differentiation of uncommitted naive T-cells into anti-inflammatory Foxp3(+) Tregs or proinflammatory ROR gamma t(+) Th17 cell population and thereby can modulate autoimmune, immunopathological, and transplantation reactions.