Continuous stimulation by normal luminal bacteria is essential for the development and perpetuation of colitis in Tgϵ26 mice

Background & Aims: Normal resident bacteria are required for development of colitis in several rodent models. We determined whether bacterial stimulation is necessary for both induction and perpetuation of mucosal inflammation and T-cell activation in Tgϵ26 mice, in which transplantation of wild-type bone marrow (BM⇒Tgϵ26) causes colitis under specific pathogen–free (SPF) conditions. Methods: BM from (C57BL/6 × CBA/J) F1 mice was transplanted into germfree (GF) or SPF Tgϵ26 mice. Mesenteric lymph node (MLN) cells from these mice were then transferred into SPF or GF recipients. Colitis and activation of MLN cells were measured by histologic scores, membrane marker analysis, and intracellular cytokine staining. Cytokine secretion by MLN cells stimulated by anti-CD3 or by luminal or epithelial antigens was measured by ELISA. Results: Colitis did not develop when BM was transferred into GF recipient mice (BM⇒GF Tgϵ26). T lymphocytes that secreted interferon γ upon activation were present in the MLN of BM⇒GF Tgϵ26 mice, albeit in lower frequency than in control BM⇒SPF Tgϵ26 mice. Furthermore, transfer of MLN cells from BM⇒SPF Tgϵ26 mice into SPF Tgϵ26 recipients induced active colitis, but not if the same cells were transferred into GF Tgϵ26 recipients. Although CD4 T cells were detected in the colonic mucosa of GF recipients, no inflammation was observed for at least 31 weeks. In a reciprocal experiment, MLN cells from BM⇒GF Tgϵ26 mice without colitis transferred disease to SPF Tgϵ26 recipients within 2–4 weeks. Conclusions: Activated T cells are present in the mucosa of BM⇒GF Tgϵ26 mice but are incapable of inducing disease unless colonic bacteria are present. Moreover, pathogenic T cells require the continuous presence of colonic bacteria to sustain colitis. GASTROENTEROLOGY 2001;120:900-913