Lineage targeted MHC-II transgenic mice demonstrate the role of dendritic cells in bacterial-driven colitis

Inflamm Bowel Dis. 2013 Jan;19(1):174-84. doi: 10.1002/ibd.23000.

Abstract

Background: Inflammatory bowel disease (IBD) pathogenesis involves an inadequately controlled immune reaction to intestinal microbiota, and CD4(+) T cells, dependent on 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 [DCs]) and nonprofessional APC (intestinal epithelial cells [IECs]) in microbial-driven intestinal inflammation remains controversial.

Methods: We generated transgenic animals on an MHC-II(-/-) genetic background in which MHC-II is expressed on 1) DC via the CD11c promoter (CD11cTg) or 2) 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 3 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 3 weeks and even after 16 weeks post-AT 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 3 weeks of AT. Expression of MHC-II solely on IEC in the presence of a microbial trigger and T cells was insufficient to trigger severe colitis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adoptive Transfer
  • Animals
  • Blotting, Western
  • CD11c Antigen / genetics
  • CD4-Positive T-Lymphocytes / immunology
  • CD4-Positive T-Lymphocytes / microbiology
  • Colitis / etiology*
  • Colitis / pathology
  • DNA-Binding Proteins / physiology
  • Dendritic Cells / immunology*
  • Dendritic Cells / microbiology
  • Epithelial Cells / immunology*
  • Epithelial Cells / microbiology
  • Female
  • Flow Cytometry
  • Helicobacter
  • Helicobacter Infections / genetics
  • Helicobacter Infections / immunology*
  • Helicobacter Infections / microbiology
  • Histocompatibility Antigens Class II / genetics*
  • Host-Pathogen Interactions
  • Immunity, Innate / immunology
  • Immunoenzyme Techniques
  • Immunophenotyping
  • Inflammation / genetics
  • Inflammation / immunology*
  • Inflammation / microbiology
  • Mice
  • Mice, Transgenic
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes, Regulatory / immunology
  • T-Lymphocytes, Regulatory / microbiology

Substances

  • CD11c Antigen
  • DNA-Binding Proteins
  • Histocompatibility Antigens Class II
  • RNA, Messenger
  • Rag2 protein, mouse