Lineage Targeted MHC-II Transgenic Mice Demonstrate the Role of Dendritic Cells in Bacterial-driven Colitis

Abstract

Background Inflammatory bowel disease (IBD) pathogenesis involves an inadequately controlled immune reaction to intestinal microbiota and CD4+ T cells, dependent upon MHC class II (MHC-II) processing and presentation by antigen presenting cells (APC), play important roles The role of professional APC (macrophages and dendritic cells (DC)) and nonprofessional APC (intestinal epithelial cells (IEC)) in microbial driven intestinal inflammation remains controversial. Methods We generated transgenic animals on a MHC-II−/− genetic background in which MHC-II is expressed on a) DC via the CD11c promoter (CD11cTg) or b) IEC via the fatty acid binding protein (liver) promoter (EpithTg). These mice were crossed with Rag2−/− mice to eliminate T and B cells (CD11cTg/Rag2−/− and EpithTg/Rag2−/−). Helicobacter bilis (Hb) infection and adoptive transfer (AT) of naïve CD4+ T cells were used to trigger IBD. Results CD11cTg/Rag2−/− mice infected with Hb+AT developed severe colitis within three weeks post AT, similar to disease in positive control Rag2−/− mice infected with Hb+AT. CD11cTg/Rag2−/− mice given AT alone or Hb alone had significantly less severe colitis. In contrast, EpithTg/Rag2−/− mice infected with Hb+AT developed mild colitis by three weeks and even after 16 weeks post adoptive transfer, had only mild lesions. Conclusions MHC-II expression restricted to DCs is sufficient to induce severe colitis in the presence of T cells and a microorganism such as Hb within three weeks of adoptive transfer. Expression of MHC-II solely on IEC in the presence of a microbial trigger and T cells was insufficient for triggering severe colitis.

Epithelial MHC Class II Expression and Its Role in Antigen Presentation in the Gastrointestinal and Respiratory Tracts

“…Maggio-Price et al induced colonic inflammation in RAG2 −/− mice exclusively expressing MHC class II either on IECs or DCs. Animals with MHC class II + DCs developed severe colitis, whereas mice with MHC class II on IECs developed only mild inflammation ( 125 ). Additionally, mice lacking MHC class II on DCs appeared to develop intestinal inflammation due to lack of proper CD4 + T cell-mediated adaptive immune responses to commensal bacteria, as gnotobiotic mice under the same conditions did not develop inflammation ( 126 ).…”

Smad nuclear interacting protein 1 (SNIP1) inhibits intestinal inflammation through regulation of epithelial barrier function

“…[5][6][7] A monolayer of IEC not only forms a physical barrier separating host from luminal environment, but also interacts with other immune cells, such as T cells and dendritic cells. [8][9][10] An impaired epithelial barrier provides the opportunity for gut microbiota invasion and causes intestinal inflammation. However, it is still not completely clear how intestinal epithelial barrier is regulated.…”

Role of Epithelial Cells in Antigen Presentation

“…However, regulatory T cells were also induced in the respective mouse models in response to epithelial MHC class II presentation and may have contributed to the control of intestinal inflammation ( Westendorf et al, 2006( Westendorf et al, , 2009. The concept of regulatory functions of IEC-dependent MHC class II restricted Ag presentation in vivo was further supported by two studies, which demonstrated that epithelial MHC class II expression in mice does not contribute to infection-induced colitis, but instead elicits regulatory effects associated with protection from intestinal inflammation (Maggio-Price et al, 2013;Thelemann et al, 2014). Thus, intestinal epithelial MHC class II restricted Ag presentation can initiate both proinflammatory as well as regulatory T cell responses.…”