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, GF3SPF 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.
ASJC Scopus subject areas
- Immunology and Allergy