Gut‐homing CD4⁺ T cell receptor αβ⁺ T cells in the pathogenesis of murine inflammatory bowel disease

Abstract

We studied which T cell subsets from the gut-associated lymphoid tissue (GALT) can migrate out of the gut mucosa and repopulate GALT compartments of an immunodeficient (semi)syngeneic host. Many distinct lymphocyte subsets were found in GALT of immunocompetent H-2d (BALB/c, BALB/cdm2, C.B-17+/+) mice. No antigen receptor-expressing lymphoid cells were found in GALT of congenic C.B-17 scid/scid (scid) mice. The heterotopic transplantation of a full-thickness gut wall graft from the ileum or colon of immunocompetent (C.B-17+/+, BALB/cdm2) donor mice onto immunodeficient scid mice selectively reconstituted a CD3+ T cell receptor alpha beta+ CD4+ T cell subset. CD4+ cells of this subset expressed the surface phenotype of mucosa-seeking, memory T cells. In the immunodeficient scid host, this gut-derived CD4+ T cell subset was found in spleen, peritoneal cavity, mesenteric lymph nodes (LN), epithelial layer and lamina propria of the small and large intestine, but not in peripheral LN. Scid mice heterotopically transplanted with gut from a congenic, immunocompetent donor developed clinical and histological signs of inflammatory bowel disease (IBD). Hence, the selective repopulation of GALT compartments with CD4+ T cells from normal GALT plays an essential role in the pathogenesis of IBD in an immunodeficient host.

MHC-II-Independent CD4+ T Cells Induce Colitis in Immunodeficient RAG−/− Hosts

“…This has been demonstrated in H-2 d mice of the BALB/c background (1)(2)(3)(4)(5) and in H-2 b mice of the C57BL/6 (B6) background (6 -8). The key factors for the development of an IBD in these models are an inducing CD3 ϩ…”

CD4+VEGFR1HIGH T cell as a novel Treg subset regulates inflammatory bowel disease in lymphopenic mice

“…CD4 1 T cells transferred into immune-deficient mice lead to IBD in response to enteric bacterial antigens derived from commensal microorganism, causing lethal weight loss and diarrhea due to endothelial and crypt hyperplasia as well as significant accumulation of lymphocytes, neutrophils, and macrophages within the lamina propria in the large intestine. 31,[59][60][61][62] In most human and mouse cases examined, IBD is associated with Th1-producing TNF and IFN-c, which are important mediators of this disease. 63,64 Th17 cells also have been suggested to play a key role in the pathogenesis of colitis and IBD, as they convert into Th1 cells and promote Th1 responses through IL-12 and IL-23.…”

Defective expression of gp180, a novel CD8 ligand on intestinal epithelial cells, in inflammatory bowel disease.

“…Here, too, CD4ϩ T cells appear to play a significant role in the induction of colitis. Rudolphi and co-workers (29) have shown that intestinal CD4ϩ T cells from normal mice home preferentially to the intestinal mucosa and trigger disease upon transfer into severe combined immunodeficient (SCID) mice. Intriguingly, and Morrissey et al (33) have defined specific subpopulations of normal CD4ϩ T cells, expressing high or low amounts of CD45RB, which have the capacity to induce or prevent colonic inflammatory disease, respectively, upon transfer into SCID mice.…”