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

SUMMARY: Initial lesions in inflammatory bowel disease induced during the repopulation of immunodeficient RAG1-/-mice with immunocompetent CD4 ϩ T cells have not been previously described. In this transfer colitis model, we followed CD4 ϩ T cell repopulation in the host by injecting autofluorescent CD4 ϩ 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 ϩ CD4 ϩ 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 ϩ macrophages were excluded. At Days 8 to 11 posttransfer (before colitis was manifest), CD4 ϩ T cells clustered and proliferated in CD11c ϩ 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 ϩ T cell/DC aggregates. (Lab Invest 2001, 81:1339 -1349.

Foxp3-Expressing CD103+ Regulatory T Cells Accumulate in Dendritic Cell Aggregates of the Colonic Mucosa in Murine Transfer Colitis

“…The different IBD intensities in both groups were confirmed by means of a semiquantitative colitis score ( Figure 1C). In agreement with our earlier observations, 14 genetically labeled eGFP ϩ donor T cells accumulated in focal aggregates located in the intestinal lamina propria. This clustering was apparent in the initial phase of disease development at day 14 after transfer ( Figure 1D), before the manifestation of overt IBD.…”

“…Because Th1-biased reactions predominate in the transfer colitis model, 3 we tested if the phenotype of DC aggregates can support initiation or promotion of Th1 T-cell responses. 14 The expression of the proinflammatory cytokine IL-23, a potent signal in conferring Th1 polarization to naive T cells, 36 was marginal in ILAs and very low in the lamina propria of untransplanted mice and 2 weeks after T-cell transfer. DC aggregates may therefore have the potential to drive a Th1 reaction.…”

Role of mucosal dendritic cells in inflammatory bowel disease

“…By analyzing large numbers of such aggregates, the classification of iLA into CP and iLF was recently challenged showing that most of them display properties intermediate between CP and iLF and were termed small intestinal lymphoid tissues (siLT) [35] . In the large intestine, subepithelial DC aggregates locate in the regions of cLP where inflammation develops [36] . DC aggregates are formed by CD8α…”

A novel population of human CD56+ human leucocyte antigen D-related (HLA-DR+) colonic lamina propria cells is associated with inflammation in ulcerative colitis

“…In humans, these subsets include conventional myeloid (CD11c inflammatory sites are functionally different from those found in the tissues under steady state conditions [11,12], and studies in animal models of colitis and in human inflammatory bowel disease (IBD) suggest strongly a role for DC in driving intestinal inflammation [13,14]. In patients with active IBD, DC are reduced in number in the peripheral blood [15], but increased in the intestinal tissue [16,17], suggesting DC recruitment to and/or retention within the gastrointestinal (GI) tract during inflammation.…”