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(high)CD62L(-)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(+) TEM 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.