AbstractWe previously demonstrated that IL‐7 is essential for the persistence of T‐cell‐mediated colitis, by showing that adoptive transfer of CD4+CD45RBhigh 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+CD45RBhigh 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.