Bone marrow-mesenchymal stem cells are a major source of interleukin-7 and sustain colitis by forming the niche for colitogenic CD4 memory T cells

Abstract

ObjectiveInterleukin (IL)-7 is mainly produced in bone marrow (BM) that forms the niche for B cells. We previously demonstrated that BM also retains pathogenic memory CD4 T cells in murine models of inflammatory bowel disease (IBD). However, it remains unknown whether BM-derived IL-7 is sufficient for the development of IBD and which cells form the niche for colitogenic memory CD4 T cells in BM.DesignTo address these questions, we developed mice in which IL-7 expression was specific for BM, and identified colitis-associated IL-7-expressing mesenchymal stem cells (MSC) in the BM.ResultsIL-7–/–×RAG-1–/– mice injected with BM cells from IL-7+/+×RAG-1–/– mice, but not from IL-7–/–×RAG-1–/– mice, expressed IL-7 in BM, but not in their colon, and developed colitis when injected with CD4+CD45RBhigh T cells. Cultured BM MSC stably expressed a higher level of IL-7 than that of primary BM cells. IL-7-sufficient, but not IL-7-deficient, BM MSC supported upregulation of Bcl-2 in, and homeostatic proliferation of, colitogenic memory CD4 T cells in vitro. Notably, IL-7–/–×RAG-1–/– mice transplanted with IL-7-sufficient, but not IL-7-deficient, BM MSC expressed IL-7 in BM, but not in their colon, and developed colitis when transplanted with CD4+CD45RBhigh T cells.ConclusionsWe demonstrate for the first time that BM MSC are a major source of IL-7 and play a pathological role in IBD by forming the niche for colitogenic CD4 memory T cells in BM.

Cooperation between IL-7 Receptor and Integrin α2β1 (CD49b) Drives Th17-Mediated Bone Loss

“…2A). Second, IL-7 is a critical cytokine for effector/memory T cell survival, IL-7 levels produced by bone marrow stromal cells increase in bone loss-associated diseases like RA (11,27,28), and IL-7 has been involved with survival of memory CD4 + T cells in the bone marrow niche in colitis (42). Thus, a2b1 can provide an additional help for maintaining the survival of Th17 cells in the bone marrow of IL-7-treated mice.…”

Transplantation of bone marrow-derived mesenchymal stem cells facilitates epithelial repair and relieves the impairment of gastrointestinal function in a rat model of enteritis

“…Instead of focusing on the potential immunosuppressive and anti-inflammatory actions of BM-MSCs in animal models of IBD as reported in recent studies [30,31], the present study tracked the homing and differentiation of transplanted BM-MSCs in the injured intestines. In IDMtreated rats, transplanted PKH26-labelled cells resided in the injured intestinal areas, mainly in the crypts and villi.…”

Mesenchymal stromal cells and chronic inflammatory bowel disease

“…In this regard, Duijvestein et al [44] have shown that in vitro MSCs activation by INFγ increases the immunosuppressive capacity of cells and their in vivo therapeutic efficacy in mice with colitis induced by trinitrobenzene sulfonate. On the other hand, Nemoto et al [47], in a murine model, have shown that bone marrow MSCs constitute the main source of IL-7 production, and may play an etiopathogenic role in IBD by forming a niche for colitogenic CD4+ memory T cells in bone marrow.…”