Long-lived colitogenic CD4⁺ memory T cells residing outside the intestine participate in the perpetuation of chronic colitis

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⁺CD45RB^high 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 CD44^highCD62L^-IL-7Rα^high 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.