Bone Marrow Retaining Colitogenic CD4⁺ T Cells May Be a Pathogenic Reservoir for Chronic Colitis

Background & Aims: Although bone marrow (BM) is known as a primary lymphoid organ, it also is known to harbor memory T cells, suggesting that this compartment is a preferential site for migration and/or selective retention of memory T cells. We here report the existence and the potential ability to induce colitis of the colitogenic BM CD4⁺ memory T cells in murine colitis models. Methods: We isolated BM CD4⁺ T cells obtained from colitic severe combined immunodeficient mice induced by the adoptive transfer of CD4⁺CD45RB^high T cells and colitic interleukin (IL)-10^-/- mice that develop colitis spontaneously, and analyzed the surface phenotype, cytokine production, and potential activity to induce colitis. Furthermore, we assessed the role of IL-7 to maintain the colitogenic BM CD4⁺ T cells. Results: A high number of CD4⁺ T cells reside in the BM of colitic severe combined immunodeficient mice and diseased IL-10^-/- mice, and they retain significant potential to induce type-1 T helper-mediated colitis in an IL-7-dependent manner. These resident BM CD4⁺ T cells have an effector memory (T_EM; CD44^highCD62L^-IL-7R^high) phenotype and preferentially are attached to IL-7-producing BM cells. Furthermore, the accumulation of BM CD4⁺ T_EM cells was decreased significantly in IL-7-deficient recipients reconstituted with the colitogenic lamina propria CD4⁺ T_EM cells. Conclusions: Collectively, these findings suggest that BM-retaining colitogenic CD4⁺ memory T cells in colitic mice play a critical role as a reservoir for persisting lifelong colitis.