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

Tzu-Yu Shao,Bor-Luen Chiang,Ling-Hui Hsu,Chien-Hui Chien

doi:10.1038/srep32415

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.

Highlights

Recent studies have revealed various forkhead box P3 (Foxp3)− regulatory T (Treg) cell subsets effectively protect mice from colitis
We demonstrated that splenic B cells and peritoneal B-1a cells as well as Peyer’s patch B cells induced Treg-of-B cells that have many Treg-associated features, such as the production of IL-10 and the expression of CD25, cytotoxic T lymphocyte antigen 4 (CTLA4), inducible costimulator (ICOS), OX40 (CD134), programmed death-1 (PD-1), glucocorticoid-induced tumor necrosis factor receptor (GITR), and LAG37–9,27
We investigated the characteristics and regulatory function of Treg-of-B cells and examined whether IL-10 is necessary for the protective effects

Summary

Result

To address whether the addition of Treg-of-B cells can suppress inflammatory cytokine production in the colons of mice adoptively transferred with colitogenic T cells, the levels of cytokines in cultured supernatant from colon explants and mesenteric lymph nodes (MLNs) were assessed. The levels of both IFN-γand IL-1βin colon cultures significantly decreased in mice that had received either CD4+CD45RBlo or Treg-of-B cells, and there were no significant differences between these groups (Fig. 3A). There was no difference between the mice that had received WT Treg-of-B cells and those that received IL-10 KO Treg-of-B cells

Discussion

Findings

Methods