Mesenchymal stem cells ameliorate B-cell-mediated immune responses and increase IL-10-expressing regulatory B cells in an EBI3-dependent manner

摘要

Effector B cells are central contributors to the development of autoimmune disease by activating autoreactive T cells,producing pro-inflammatory cytokines and organizing ectopic lymphoid tissue.Conversely,IL-10-producing regulatory B(Breg)cells have pivotal roles in maintaining immunological tolerance and restraining excessive inflammation in autoinflammatory disease.Thus,regulating the equilibrium between antibody-producing effector B cells and Breg cells is critical for the treatment of autoimmune disease.In this study,we investigated the effect of human palatine tonsil-derived mesenchymal stem cells(T-MSCs)on estradiol(E2)-induced B-cell responses in vivo and in vitro.Transplantation of T-MSC into E2-treated mice alleviated B-cell-mediated immune responses and increased the population of IL-10-producing Breg cells.T-MSCs regulated the B-cell populations by producing Epstein–Barr virus(EBV)-induced 3(EBI3),one of the two subunits of IL-35 that is the well-known inducer of Breg cells.We demonstrate a critical role of EBI3(IL-35)in vitro by depleting EBI3 in T-MSCs and by adding exogenous IL-35 to the culture system.Taken together,our data suggest that IL-35-secreting MSCs may become an attractive therapeutic to treat B-cell-mediated autoimmune diseases via expanding Breg cells.