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Induction of Murine Intestinal Inflammation by Adoptive Transfer of Effector CD4+CD45RBhigh T Cells into Immunodeficient Mice
Published on: April 21, 2015
Nucleotide binding oligomerization domain 2 deficiency leads to dysregulated TLR2 signaling and induction of
Tomohiro Watanabe1, Atsushi Kitani, Peter J Murray
1Mucosal Immunity Section, Laboratory of Host Defenses, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 10-CRC, Room 5W3940, 10 Center Drive, Bethesda, Maryland 20892, USA.
Abstract:
In this study, we determined conditions leading to the development of colitis in mice with nucleotide binding oligomerization domain 2 (NOD2) deficiency, a susceptibility factor in Crohn's disease. We found that NOD2-deficient antigen-presenting cells (APCs) produced increased amounts of interleukin (IL)-12 in the presence of ovalbumin (OVA) peptide and peptidoglycan or recombinant E. coli that express OVA peptide (ECOVA). Furthermore, these APCs elicited heightened interferon-gamma (IFN-gamma) responses from cocultured OVA-specific CD4+ T cells. We then demonstrated that NOD2-deficient mice adoptively transferred OVA-specific CD4+ T cells and that administered intrarectal ECOVA developed colitis associated with the expansion of OVA-specific CD4+ T cells producing IFN-gamma. Importantly, this colitis was highly dependent on Toll-like receptor 2 (TLR2) function since it was suppressed in NOD2 and TLR2 double-deficient mice. Thus, NOD2-deficient mice become susceptible to colitis as a result of increased TLR2 responses when they have the capacity to respond to an antigen expressed by mucosal bacteria.
Insights
Mice lacking nucleotide binding oligomerization domain 2 (NOD2) develop colitis when exposed to specific bacterial antigens. This condition is linked to increased Toll-like receptor 2 (TLR2) activity and interferon-gamma production.
Area of Science:
- Immunology
- Gastroenterology
- Microbiology
Background:
- Nucleotide binding oligomerization domain 2 (NOD2) deficiency is a known susceptibility factor for Crohn's disease.
- Understanding the mechanisms underlying NOD2-related inflammatory conditions is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the conditions that precipitate colitis in mice with NOD2 deficiency.
- To elucidate the role of antigen-presenting cells (APCs) and immune responses in NOD2-deficient mice.
Main Methods:
- NOD2-deficient mice were used to study colitis development.
- Antigen-presenting cells (APCs) were stimulated with ovalbumin (OVA) peptide and bacterial components.
- Interferon-gamma (IFN-gamma) production by CD4+ T cells was measured.
- Adoptive transfer of OVA-specific CD4+ T cells and intrarectal administration of recombinant E. coli expressing OVA (ECOVA) were performed.
- The role of Toll-like receptor 2 (TLR2) was assessed using double-deficient mice.
Main Results:
- NOD2-deficient APCs produced elevated levels of interleukin (IL)-12 upon stimulation.
- These APCs induced heightened IFN-gamma responses in OVA-specific CD4+ T cells.
- NOD2-deficient mice receiving OVA-specific CD4+ T cells and ECOVA developed colitis characterized by IFN-gamma-producing T cells.
- Colitis development was significantly suppressed in NOD2 and TLR2 double-deficient mice.
Conclusions:
- NOD2 deficiency predisposes mice to colitis, particularly when exposed to antigens from mucosal bacteria.
- The development of colitis in this model is dependent on heightened TLR2 responses.
- This study highlights the intricate interplay between NOD2, TLR2, and immune responses in intestinal inflammation.
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