Colitogenic CD4⁺ effector-memory T cells actively recirculate in chronic colitic mice

Background: Although the clinical usefulness of leukocytapheresis for patients with inflammatory bowel disease (IBD) has been reported as a selective removal therapy targeting pathogenic immune cells in blood circulation, it remains unclear whether colitogenic CD4⁺ T cells continuously recirculate in peripheral blood during the chronic phase of colitis. Methods: To resolve this question we conducted a series of in vivo experiments using a murine chronic colitis model induced by adoptive transfer of CD4⁺CD45RB^high cells into SCID mice in combination with a parabiosis system. Results: In colitic SCID recipients, first, almost all CD4⁺ CD45RB^high donor cells were converted to CD4⁺CD44^highCD62L^- IL-7Rα ^high effector-memory T (T_EM) cells at 8 weeks after transfer and were distributed throughout the whole body, including colonic lamina propria, mesenteric lymph nodes, thoracic duct, peripheral blood, spleen, and bone marrow. Second, SCID mice retransferred with the colitic peripheral blood CD4⁺ T cells developed colitis that is identical to the original colitis. Third, CD4⁺ cells in parabionts between established colitic RAG-2^-/- mice induced by adoptive transfer of Ly5.1⁺ or Ly5.2⁺ CD4⁺CD45RB^high T cells were well mixed in almost equal proportions at various sites 2 weeks after parabiosis surgery, and the redistribution of Ly5.1⁺ and Ly5.2⁺ CD4⁺ T cells was significantly suppressed in FTY720-treated parabionts. Conclusions: Together, these findings indicate that colitogenic CD4⁺ TEM cells continuously recirculate in established colitic mice, suggesting that therapeutic approaches targeting systemic CD4⁺ T_EM cells, such as bone marrow transplantation, rather than those targeting only intestinal CD4⁺ T cells, may be feasible for the treatment of IBD.