CD11c+ (F4/80 -CD68 -) dendritic cells (DC) in the colonic lamina propria (cLP) of normal and immunodeficient (RAG1 -/-) C57BL/6 (B6) mice show high surface expression of MHC class I/ II molecules and CD1d, and low surface expression of CD40, CD80, CD86 costimulator molecules. CD4 + § g T cells from normal or MHC class II-deficient B6 mice transferred into congenic RAG1 -/-hosts induce a progressive, lethal colitis. Concomitant with colitis development, DC in the inflamed cLP increase in number and up-regulate surface expression of CD1d, MHC class II molecules and CD40, CD80, CD86 costimulator molecules. cLP DC from non-transplanted (healthy) and transplanted (diseased) mice produce similar amounts of IL-12 p70 and IL-10 in response to CD40 signaling, but the inducible IL-12 p40 release is 5-15-fold higher in mice with colitis than in non-transplanted mice. Binding of IL-12 p40 to p19 generates IL-23. Freshly isolated cLP lymphocytes (cLPL) from transplanted, diseased mice express 3-10-fold more p19 transcripts than cLPL from non-transplanted, healthy mice. p19 expression by cLPL is further up-regulated in response to CD40 ligation. Freshly isolated cLP DC from transplanted mice with colitis (but not from non-transplanted controls) stimulate IFN-+ (but not IL-4 or IL-13) release by co-cultured NKT cells. In colitis, DC accumulate in the cLP, show an activated surface phenotype, up-regulate IL-12 p40 and p19 expression, and 'spontaneously' stimulate NKT-like cells. cLP DC may be interesting targets for novel therapeutic approaches to modulate mucosal T cell responses in situ.
CD4 + § g T cell populations that develop in mice deficient in MHC class II (through 'knockout' of either the A § , or the A g chain of the I-A b molecule) comprise a major 'single-positive' (SP) CD4 + CD8 -subset (60-90%) and a minor 'double-positive' (DP) CD4 + CD8 § g + subset (10-40%). Many DP T cells found in spleen, mesenteric lymph nodes (MLN) and colonic lamina propria (cLP) express CD25, CD103 and Foxp3. Adoptive transfer of SP but not DP T cells from A § -/-or A g -/-B6 mice into congenic RAG -/-hosts induces colitis. Transfer of SP T cells repopulates the host with only SP T cells; transfer of DP T cells repopulates the host with DP and SP T cells. Anti-CD25 antibody treatment of mice transplanted with DP T cells induces severe, lethal colitis; anti-CD25 antibody treatment of mice transplanted with SP T cells further aggravates the course of severe colitis. Hence, regulatory CD25 + T cells within (or developing from) the DP T cell population of MHC class II-deficient mice control the colitogenic potential of CD25 -CD4 + T cells.
Inflammatory bowel disease (IBD) is a chronic, disabling disease. A dysregulated immune response seems to play a pivotal role in the pathogenesis of this disorder. Here we will review current concepts of the adoptive transfer model of IBD with particular emphasis on early events in disease development. In the adoptive transfer model, the reconstitution of immunoincompetent mice with CD4+ T cells from congenic donor animals leads to severe colitis. We will address the question as to which CD4+ T cell subsets might be involved in the induction, suppression, or regulation of disease, and review data concerning the specificity of their T cell receptor and its putative MHC restriction elements. We will also discuss whether and at what anatomical sites donor T cells could be primed in the recipient.
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