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^?/?×RAG‐1^?/? mice did not induce colitis; and that intestinal IL‐7 is not essential for this colitis model, by showing that IL‐7^?/?×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^?/?×RAG‐1^?/? mice were consistently diseased after separation, although no IL‐7 mRNA was detected in the tissues of separated IL‐7^?/?×RAG‐1^?/? partners. CD4⁺ T cells isolated from the separated RAG‐1^?/? or IL‐7^?/?×RAG‐1^?/? mice were then transferred into new RAG‐1^?/? or IL‐7^?/?×RAG‐1^?/? mice. Regardless of the source of donor cells, RAG‐1^?/? recipients developed colitis, whereas IL‐7^?/?×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.