Regulatory T （Treg） cells play a critical role in the maintenance of tolerance. B-la cells belong to a specific and functionally important B-cell subset that exerts its regulatory role through the production of IL-I...Regulatory T （Treg） cells play a critical role in the maintenance of tolerance. B-la cells belong to a specific and functionally important B-cell subset that exerts its regulatory role through the production of IL-IO. While IL-IO has been correlated with the induction of type 1 Treg （Trl） cells or Trl-like cells, whether IL-lO-producing B-la cells are able to induce Treg cells, especially the Trl lineage, is poorly understood. We have demonstrated that, similar to the reported B-2 cells, B-la cells are able to convert naive CD4＋CD25- T cells into a subset of T cells with suppressive function, which we called ＇Treg-of-Bla＇ cells. Treg-of-Bla cells do not express Foxp3, but upregulate the Treg markers OX40, programmed death 1 （PD-1）, inducible costimulator （ICOS） and IL-IOR. Moreover, Treg-of-Bla cells do not express Foxp3 and produce high levels of IFN-y and IL-IO, but minimal amounts of IL-4; therefore, they resemble Trl cells. However, utilizing IL-10-/- mice, we showed that IL-IO was not involved in the induction of Treg-of-Bla cells. On the contrary, CD86-mediated costimulation was essential for B-la cells to drive the induction of Treg-of-Bla cells. Finally, we demonstrated that, in contrast to the Treg cells generated by B-2 cells that mediate contact-dependent suppression, Treg-of-B la cells suppress through secreting soluble factors. While Trl cells mediate suppression mainly through IL-IO or TGF-10secretion, Treg-of-Bla cells mediate suppression through an IL-10- and TGF-10-independent pathway. Together, these findings suggest that B-la cells induce a functionally and phenotypically distinct Treg population that is dissimilar to the reported Foxp3＋ Treg or Trl cells.展开更多
Interleukin （IL）-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-la cell activity, remains to be elucidated. Here, we show tha...Interleukin （IL）-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-la cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-la cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin （Siglec）-G, an inhibitor of cell activation that is present on B-la cells. The IL-15 receptor CD122 was stimulated on B-la cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-IO is responsible for the long term survival of B-la cells in culture, which is initially promoted by IL-15. The upregulation of IL-IO was followed by the appearance of suppressor of cytokine signaling （SOCS）I in the presence of IL-15 and the loss of IL-IO. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-la cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death （PD）-I and its ligand PD-L2 were features of a predominantly IL-IO response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-la cells to mount a mucosal immune response.展开更多
文摘Regulatory T （Treg） cells play a critical role in the maintenance of tolerance. B-la cells belong to a specific and functionally important B-cell subset that exerts its regulatory role through the production of IL-IO. While IL-IO has been correlated with the induction of type 1 Treg （Trl） cells or Trl-like cells, whether IL-lO-producing B-la cells are able to induce Treg cells, especially the Trl lineage, is poorly understood. We have demonstrated that, similar to the reported B-2 cells, B-la cells are able to convert naive CD4＋CD25- T cells into a subset of T cells with suppressive function, which we called ＇Treg-of-Bla＇ cells. Treg-of-Bla cells do not express Foxp3, but upregulate the Treg markers OX40, programmed death 1 （PD-1）, inducible costimulator （ICOS） and IL-IOR. Moreover, Treg-of-Bla cells do not express Foxp3 and produce high levels of IFN-y and IL-IO, but minimal amounts of IL-4; therefore, they resemble Trl cells. However, utilizing IL-10-/- mice, we showed that IL-IO was not involved in the induction of Treg-of-Bla cells. On the contrary, CD86-mediated costimulation was essential for B-la cells to drive the induction of Treg-of-Bla cells. Finally, we demonstrated that, in contrast to the Treg cells generated by B-2 cells that mediate contact-dependent suppression, Treg-of-B la cells suppress through secreting soluble factors. While Trl cells mediate suppression mainly through IL-IO or TGF-10secretion, Treg-of-Bla cells mediate suppression through an IL-10- and TGF-10-independent pathway. Together, these findings suggest that B-la cells induce a functionally and phenotypically distinct Treg population that is dissimilar to the reported Foxp3＋ Treg or Trl cells.
文摘Interleukin （IL）-15 is known to strongly modulate T-cell function; however, its role in controlling mucosal immunity, including its ability to modulate B-la cell activity, remains to be elucidated. Here, we show that IL-15 upregulates activation molecules and the costimulatory molecule CD80 on viable B-la cells. Cell activation was accompanied by the depletion of sialic acid-binding immunoglobulin-like lectin （Siglec）-G, an inhibitor of cell activation that is present on B-la cells. The IL-15 receptor CD122 was stimulated on B-la cells by the cytokine showing its direct involvement in IL-15-mediated responses. IL-IO is responsible for the long term survival of B-la cells in culture, which is initially promoted by IL-15. The upregulation of IL-IO was followed by the appearance of suppressor of cytokine signaling （SOCS）I in the presence of IL-15 and the loss of IL-IO. This resulted in the cells switching to IL-12 expression. This anti-inflammatory to pro-inflammatory shift in the B-la cell character was independent of the cell-specific marker CD5, which remained highly expressed throughout the in vitro life of the cells. The presence of the immunosuppressive receptor programmed cell death （PD）-I and its ligand PD-L2 were features of a predominantly IL-IO response. PD-1 and PD-L2 can mediate juxtacrine signaling. However, the abrogation of PD-1 and its ligand was observed when the cells expressed IL-12. This demonstrates an inverse relationship between the receptor and ligand and the pro-inflammatory cytokine. The induction of IgM and IgA, which can play pivotal roles in mucosal immunity, was promoted in the presence of IL-15. Collectively, the data implicate IL-15 as the master cytokine that induces B-la cells to mount a mucosal immune response.
