IL-7 exacerbates chronic colitis with expansion of memory IL-7RhighCD4+mucosal T cells in mice

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Abstract
We have previously demonstrated that mucosal CD4+ T cells expressing high levels of IL-7 receptor (IL-7Rhigh) are pathogenic cells responsible for chronic colitis. Here we investigate whether IL-7 is directly involved in the expansion of IL-7Rhigh memory CD4+ mucosal T cells and the exacerbation of colitis. We first showed that CD4+ lamina propria lymphocytes (LPLs) from wild-type, T cell receptor-α-deficient (TCR-α−/−), and recombinase-activating gene (RAG)-2−/−-transferred mice with or without colitis showed phenotypes of memory cells, but only CD4+ LPLs from colitic mice showed IL-7Rhigh. In vitro stimulation by IL-7, but not by IL-15 and thymic stromal lymphopoietin, enhanced significant proliferative responses and survival of colitic CD4+, but not normal CD4+ LPLs. Importantly, in vivo administration of IL-7 mice accelerated the expansion of IL-7Rhigh memory CD4+ LPLs and thereby exacerbated chronic colitis in RAG-2−/− mice transferred with CD4+ LPLs from colitic TCR-α−/− mice. Conversely, the administration of anti-IL-7R monoclonal antibody significantly inhibited the development of TCR-α−/− colitis with decreased expansion of CD4+ LPLs. Collectively, the present data indicate that IL-7 is essential for the expansion of pathogenic memory CD4+ T cells under pathological conditions. Therefore, therapeutic approaches targeting the IL-7R pathway may be feasible in the treatment of human inflammatory bowel disease.