Long-Lived Colitogenic CD4+ Memory T Cells Residing Outside the Intestine Participate in the Perpetuation of Chronic Colitis

Abstract

To understand the perpetuation of inflammatory bowel disease (IBD), it is important to clarify whether the colitogenic CD4+ T cells are self-limited effector or long-lived memory T cells. We here investigate the latency of colitogenic CD4+ T cells in the remission stage of colitis under germfree (GF) conditions. We isolated splenic (SP) CD4+ T cells from colitic CD4+CD45RBhigh T cell-injected SCID mice maintained under specific pathogen-free (SPF) conditions and transferred them into SPF or GF SCID mice. Donor colitic SP CD4+ T cells have a characteristic CD44highCD62L−IL-7Rαhigh effector-memory T-type phenotype. Six weeks after transfer of cells to GF SCID mice, one group of mice was continued in GF conditions (GF→GF), and the other was transferred into SPF conditions (GF→SPF). GF→SPF but not GF→GF SCID mice developed colitis with elevated production of Th1 and Th17 cytokines at 4 wk after transfer. Surprisingly, a large number of CD4+ effector-memory T cells and a small but substantial number of central-memory T cells remained resident in SP and bone marrow, but not in lamina propria, of the GF→GF SCID recipients. Consistent with this, GF→SPF but not GF→GF SCID mice rapidly developed colitis. Taken together, these findings suggest that long-lived colitogenic memory CD4+ cells can be established even in the presence of commensal Ags, reside outside the intestine in the absence of commensal bacteria, and participate in the perpetuation of colitis. Thus, blocking a stimulus of colitogenic memory CD4+ cells such as IL-7 may have therapeutic benefit for treatment of inflammatory bowel disease.

CCR9+ plasmacytoid dendritic cells in the small intestine suppress development of intestinal inflammation in mice

“…In the colon, the commensal bacteria are approximately 100-fold denser than in the SI [14]. Consistently, germ-free rag-2 −/− transferred with CD4 + CD45RB high T cells did not develop colitis and ileitis [15], suggesting that colitis is dominantly mediated along with commensal bacteria, while ileitis may be dependent on other factors.…”

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

“…Because the spleen and lymph nodes are dispensable for the development of chronic colitis,13 we found that BM is the main source of IL-7 14 15. We previously demonstrated that, in addition to a major subpopulation of T EM cells, a substantial proportion of colitogenic CD4 central memory cells preferentially reside in the BM of colitic mice 16 17. Importantly, these resident BM CD4 memory T cells are closely associated with IL-7-producing stromal cells and retain a significant potential to induce colitis after adoptive retransfer into new SCID/RAG-2 –/– mice.…”

Mucosal Resident Memory CD4 T Cells in Protection and Immunopathology

“…T H 1 and T H 17 cells have both been implicated in the pathogenesis of the disease. In experimental models of IBD circulating colitogenic memory CD4 T cells required the presence of gut commensals to induce inflammation and IBD pathogenesis (86). In mouse models of IBD transfer experiments of gut CD4 TRM transferred disease to RAG2 −/− mice (87).…”