Novel Foxp3− IL-10− Regulatory T-cells Induced by B-Cells Alleviate Intestinal Inflammation in Vivo

Abstract

Recent studies have revealed various Foxp3− regulatory T (Treg) cell subsets effectively protect mice from colitis. In the present study, we demonstrated that B cells induced a particular subset of regulatory T (Treg-of-B) cells, expressing programmed cell death 1 (PD-1), inducible costimulator (ICOS), lymphocyte-activation gene 3 (LAG3), glucocorticoid-induced tumor necrosis factor receptor (GITR), and OX-40, did not express Foxp3. Treg-of-B cells produced abundant levels of IL-10 and low levels of IL-4 and TGF-β. Adoptive transfer of Treg-of-B cells protected mice from CD4+CD45RBhi T-cell-induced colitis, including infiltration of leukocytes, depletion of goblet cells, epithelial hyperplasia, and inhibition of Th1 and Th17 cytokines. These features were similar to IL-10-producing type 1 regulatory T (Tr1) cells; however, IL-10-deficient Treg-of-B cells maintained their suppressive function in vitro as well as in vivo, while the regulation of Tr1 cells depended on IL-10. In conclusion, Treg-of-B cells protected against experimental colitis through an IL-10-independent mechanism. We reported a novel subpopulation of regulatory T cells was different from conventional Foxp3+ Treg and IL-10-producing Tr1 cells.

Characterization of c-Maf+Foxp3− Regulatory T Cells Induced by Repeated Stimulation of Antigen-Presenting B Cells

“…Treg-of-B cells have been demonstrated that protected mice from allergic asthma, arthritis, and inflammatory bowel disease2830313233. Peptide-induced antigen-specific Treg-of-B cells and monoclonal antibodies induced non-antigen-specific Treg-of-B cells possessed suppressive function.…”

Recent advances in regulatory T cells induced by B cells

“…Moreover, Treg-of-B cells exerted IL-10-independent suppressive abilities and differed from Tr1 cells that mainly rely on IL-10-mediated inhibition. 6,7 These findings indicated that Treg-of-B cells have a regulatory T-related phenotype and new characteristics from the well-established Foxp3 + regulatory T cells and IL-10-dominant Tr1 cells.…”

The expanding family of noncanonical regulatory cell subsets

“…Indeed, it was shown that a mature immunologic synapse formed between naïve B cells and naïve T cells plays a key role in their suppressive activities. As for specific markers, Treg‐of‐B cells are characterized by high levels of Treg‐related molecules, such as CD44, GITR, ICOS, LAG3, and OX40, low levels of PD‐1 plus CTLA‐4 and no expression of Foxp3, Helios, and neuropilin‐1 . Also, Treg‐of‐B cells can produce large amounts of IL‐10, IL‐4, and TGF‐β compared to naïve T cells.…”

“…While dendritic cell stimulation generates classical effector T cells, naïve B‐cell‐activated T cells show regulatory capacity in vitro and in vivo. Therapeutic effects of Treg‐of‐B cells have been described in several murine disease models, including intestinal inflammation, allergic asthma, and rheumatoid arthritis . The results of these trials suggest that Treg‐of‐B cells are beneficial for the treatment of a wide variety of diseases, although the clinical potential of Treg‐of‐B cells is just beginning to be realized.…”

“…Majorly contact-dependent 23 B cells, and CD9 may be taken as a reliable marker for defining both mouse and human Bregs, although not yet generally accepted in the literature.…”