A B-la cell subset induces Foxp3- T cells with regulatory activity through an IL-10-independent pathway

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.