Clustering of colonic lamina propria CD4+ T cells to subepithelial dendritic cell aggregates precedes the development of colitis in a murine adoptive transfer model

Abstract

Initial lesions in inflammatory bowel disease induced during the repopulation of immunodeficient RAG1-/- mice with immunocompetent CD4+ T cells have not been previously described. In this transfer colitis model, we followed CD4+ T cell repopulation in the host by injecting autofluorescent CD4+ T cells from congenic, enhanced green fluorescent protein (eGFP)-transgenic mice. This allowed the direct, sensitive, and unambiguous histological detection of the repopulation of the intestinal tract, mesenteric lymph nodes, and spleen of the host with donor eGFP+ CD4+ T cells. We identified in RAG1-/- mice intestinal dendritic cell (DC) aggregates under the basal crypt epithelium at the mucosa/submucosa junction from which F4/80+ macrophages were excluded. At Days 8 to 11 posttransfer (before colitis was manifest), CD4+ T cells clustered and proliferated in CD11c+ DC aggregates. T cell clustering was most pronounced in the cecum where histologically overt colitis became manifest 5 to 10 days later. Junctional DC aggregates were thus prevalent in the triggering phase of the disease. The data suggest that pathogenic T cell responses inducing inflammatory bowel disease are primed or restimulated in situ in junctional CD4+ T cell/DC aggregates.