Lineage Targeted MHC-II Transgenic Mice Demonstrate the Role of Dendritic Cells in Bacterial-driven Colitis
| Autor: | Mingzu Lei, Thea Brabb, Audrey Seamons, Robert M. Hershberg, Lillian Maggio-Price, Helle Bielefeldt-Ohmann, Weiping Zeng, Carol B. Ware |
|---|---|
| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Naive T cell T cell Blotting Western Antigen presentation CD1 Mice Transgenic Biology Real-Time Polymerase Chain Reaction T-Lymphocytes Regulatory Article Helicobacter Infections Immunophenotyping Immunoenzyme Techniques Mice Antigen Helicobacter medicine Animals Immunology and Allergy Cytotoxic T cell RNA Messenger Antigen-presenting cell Inflammation CD40 Reverse Transcriptase Polymerase Chain Reaction Histocompatibility Antigens Class II Gastroenterology Epithelial Cells Dendritic Cells Colitis Flow Cytometry Adoptive Transfer Immunity Innate CD11c Antigen DNA-Binding Proteins medicine.anatomical_structure Host-Pathogen Interactions Immunology biology.protein Female |
| Zdroj: | Inflammatory Bowel Diseases. 19:174-184 |
| ISSN: | 1078-0998 |
| DOI: | 10.1002/ibd.23000 |
| Popis: | Inflammatory bowel diseases (IBD) encompass several related chronic inflammatory disorders of the gastrointestinal tract, notably ulcerative colitis (UC) and Crohn’s disease (CD).1 While CD and UC are distinct from a clinical and histopathological standpoint, important themes have emerged over the past two decades linking their pathogenesis to aberrant T cell immune responses in the intestinal mucosa. These inflammatory T cell responses arise from a complex interaction between host genetics and the diverse microbiota present within the lumen of the intestinal tract. Data from a variety of animal models highlight the importance of CD4+ T cells in the pathogenesis of 2IBD.2 Perhaps the most commonly used example is the adoptive transfer model in which CD4+ T cells expressing ‘high’ levels of CD45RB induce significant intestinal inflammation in an immunocompromised host.3–6 Importantly, the inflammation observed is strictly dependent on the microbial flora, specifically the presence of commensal organisms such as Helicobacter species that are capable of triggering a pathogenic response in a susceptible host.7 Given the fact that CD4+ T cell responses are dependent on MHC II processing and presentation, these data underscore the importance of MHC II positive antigen presenting cells (APC) in the pathogenesis of IBD. Dendritic cells (DCs) are the most efficient MHC II expressing APCs with regards to processing and presentation of exogenous antigens capable of stimulating CD4+ T cell responses.8 In the adoptive transfer model of T cell mediated colitis, T cell interactions with activated DCs in the mesenteric lymph nodes (MLN) prior to the onset of disease are important for disease development.9 DCs have also been shown to interact with clusters of transferred CD4+ T cells at the basal crypt epithelium10 prior to development of signs of IBD. Although DCs play a role in priming inflammatory responses, various populations of DCs are found throughout the intestinal mucosa and also play a role in regulating inflammation and immunologic responses that are dysregulated in IBD.11, 12 It is thought that other MHC-II positive populations in the gastrointestinal tract such as epithelial cells that line mucosal surfaces and interact with luminal microbes may also contribute to the inflammatory responses characteristic of IBD depending on the context of epithelial/effector cell interactions. Intestinal epithelial cells (IECs) constitutively express MHC-II molecules, can present protein antigens on both MHC class I and class II molecules, and thus have the capacity to serve as antigen presenting cells (APCs) in the gut.13 They have been shown to serve as APCs to several populations of T cells in vitro and ex vivo13–15 and upregulate CD40 in response to inflammatory cytokines16 as well as other non-classical costimulatory molecules for lymphocyte interations.17 It has not been directly investigated whether interaction of effector cells with MHC-II expressing epithelial cells can drive IBD without the presence of other antigen presenting cells, such as DCs. Indirect evidence involving DC depletion experiments show that DCs are required for naive T cell expansion,18 which is one of the prerequisites for disease development in the adoptive transfer model of colitis.19, 20 We have developed mouse models that enabled us to determine the importance of MHC-II expression on dendritic cells or on epithelial cells in a bacterial induced adoptive transfer model of colitis. CD45RBhigh T cells were adoptively transferred into rag deficient, MHC-II deficient mice in which MHC-II was only expressed on CD11c+ cells (CD11cTg/Rag2−/−) or only on IEC via the FABPL promoter on a MHC-II−/− genetic background (EpithTg/Rag2−/−). This model system clearly demonstrated that MHC-II expressed solely on DCs was sufficient to induce robust colitis but only in the presence of a bacterial organism, Helicobacter bilis (Hb). Expression of MHC-II only on IECs was insufficient to drive severe colitis even in the presence of Hb infection. |
| Databáze: | OpenAIRE |
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