IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4+ memory T cells in chronic colitis

We previously demonstrated that IL-7 is essential for the persistence of T-cell-mediated colitis, by showing that adoptive transfer of CD4 ⁺CD45RB^high T cells into IL-7^-/- x RAG-1 ^+/+ mice did not induce colitis; and that intestinal IL-7 is not essential for this colitis model, by showing that IL-7^-/- x RAG-1^-/- mice parabiosed with colitic CD4⁺CD45RB ^high T-cell-transferred RAG-1^-/- mice developed colitis. Here, we investigated the role of IL-7 in the maintenance of colitogenic CD4⁺ T cells by surgically separating these parabionts. Surprisingly, the separated IL-7^-/- x RAG-1^-/- mice were consistently diseased after separation, although no IL-7 mRNA was detected in the tissues of separated IL-7^-/- x RAG-1^-/- partners. CD4⁺ T cells isolated from the separated RAG-1^-/- or IL-7^-/- x RAG-1^-/- mice were then transferred into new RAG-1^-/- or IL-7^-/- x RAG-1^-/- mice. Regardless of the source of donor cells, RAG-1^-/- recipients developed colitis, whereas IL-7 ^-/- x RAG-1^-/- recipients did not. Collectively, these results demonstrate that IL-7 is essential for lymphopenia-driven turnover of colitogenic CD4⁺ T cells rather than the maintenance of those cells in established colitic mice. They also provide a basis for the timing of IL-7/IL-7R blockade for the treatment of inflammatory bowel diseases.