Colitis is associated with thymic destruction attenuating CD4 ⁺25⁺ regulatory T cells in the periphery

Background & Aims: Syngeneic bone marrow transplantation into the adult tgε26 mouse results in severe wasting disease and colitis. On transplantation, the rudimentary thymus of the adult tgε26 mouse repopulates briefly but quickly regresses in temporal association with the onset of colitis. The aim of this study is to test the hypothesis that treatment of colitis restores thymic capability to generate regulatory T cells (CD4⁺25⁺ T_R cells). Methods: Colitis was induced by bone marrow transplantation into adult irradiated tgε26 mice. Colitis was prevented by 3 distinct modalities. CD4⁺25⁺ T cells were collected from both the thymus and spleen and studied for regulatory function by an in vitro suppression assay. Results: CD4⁺25 ⁺ T_R cells do not develop efficiently in the thymus of bone marrow transplanted adult tgε26 mice, which have a developmental arrest affecting thymic epithelium. By contrast, the thymic epithelium of neonatal tgε26 mice supports development of T_R cells. Consequently, colitis develops only in adult transplanted mice but not in the neonatally transplanted mice. Treatment of colitis prevents destruction of the thymus of adult transplanted tgε26 mice and TR cells are produced. Conclusions: The negative impact of colitis on T_R development in the thymus, which was confirmed in a second model of colitis, has profound implications for the pathogenesis and treatment of human inflammatory bowel disease.