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Protection against colitis by CD100-dependent modulation of intraepithelial ?? T lymphocyte function.

ABSTRACT: Intraepithelial ?? T lymphocytes (?? IEL) have important roles in repair of tissue damage at epithelial sites, such as skin and intestine. Molecules that orchestrate these ?? T-cell functions are not well defined. Recently, interaction of the semaphorin CD100 on skin ?? T cells with plexin B2 on keratinocytes was shown to be important for effective ?? T-cell function in the epidermis, which raised the possibility that CD100 may exert similar functions in the intestinal tract. In this study, we find that CD100 is expressed on all IEL, and plexin B2 is present on all epithelial cells of the mouse colon. Using the dextran sulfate sodium (DSS) mouse model of colitis, disease severity is significantly exacerbated in CD100-deficient (CD100(-/-)) mice, with increased colon ulceration and mucosal infiltration with inflammatory cells. The severe colitis in CD100(-/-) mice is attributable to the failure of the colon epithelium to mount a proliferative response to damage. Unlike wild-type ?? IEL, ?? IEL from CD100(-/-) mice fail to produce keratinocyte growth factor-1 (KGF-1) in response to DSS treatment. Administration of recombinant KGF-1 to CD100(-/-) animals ameliorates disease and reverses colitis susceptibility. These results demonstrate that CD100-mediated signals are critical for effective activation of ?? IEL to produce growth factors, including KGF-1, that are required for healing of the colon epithelium during colitis.

SUBMITTER: Meehan TF

PROVIDER: S-EPMC3795871 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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Publications

Protection against colitis by CD100-dependent modulation of intraepithelial γδ T lymphocyte function.

Meehan T F TF Witherden D A DA Kim C-H CH Sendaydiego K K Ye I I Garijo O O Komori H K HK Kumanogoh A A Kikutani H H Eckmann L L Havran W L WL

Mucosal immunology 20130522 1

Intraepithelial γδ T lymphocytes (γδ IEL) have important roles in repair of tissue damage at epithelial sites, such as skin and intestine. Molecules that orchestrate these γδ T-cell functions are not well defined. Recently, interaction of the semaphorin CD100 on skin γδ T cells with plexin B2 on keratinocytes was shown to be important for effective γδ T-cell function in the epidermis, which raised the possibility that CD100 may exert similar functions in the intestinal tract. In this study, we f ...[more]

PMID: 23695512

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Project description:UnlabelledThere is an emerging paradigm that the human microbiome is central to many aspects of health and may have a role in preventing enteric infection. Entamoeba histolytica is a major cause of amebic diarrhea in developing countries. It colonizes the colon lumen in close proximity to the gut microbiota. Interestingly, not all individuals are equally susceptible to E. histolytica infection. Therefore, as the microbiota is highly variable within individuals, we sought to determine if a component of the microbiota could regulate susceptibility to infection. In studies utilizing a murine model, we demonstrated that colonization of the gut with the commensal Clostridia-related bacteria known as segmented filamentous bacteria (SFB) is protective during E. histolytica infection. SFB colonization in this model was associated with elevated cecal levels of interleukin 17A (IL-17A), dendritic cells, and neutrophils. Bone marrow-derived dendritic cells (BMDCs) from SFB-colonized mice had higher levels of IL-23 production in response to stimulation with trophozoites. Adoptive transfer of BMDCs from an SFB(+) to an SFB(-) mouse was sufficient to provide protection against E. histolytica. IL-17A induction during BMDC transfer was necessary for this protection. This work demonstrates that intestinal colonization with a specific commensal bacterium can provide protection during amebiasis in a murine model. Most importantly, this work demonstrates that the microbiome can mediate protection against an enteric infection via extraintestinal effects on bone marrow-derived dendritic cells.ImportanceEntamoeba histolytica is the causative agent of amebiasis, an infectious disease that contributes significantly to morbidity and mortality due to diarrhea in the developing world. We showed in a murine model that colonization with the commensal members of the Clostridia known as SFB provides protection against E. histolytica and that dendritic cells from SFB-colonized mice alone can recapitulate protection. Understanding interactions between enteropathogens, commensal intestinal bacteria, and the mucosal immune response, including dendritic cells, will help in the development of effective treatments for this disease and other infectious and inflammatory diseases. The demonstration of immune-mediated protection due to communication from the microbiome to the bone marrow represents an emerging field of study that will yield unique approaches to the development of these treatments.

Dataset Information

Protection against colitis by CD100-dependent modulation of intraepithelial ?? T lymphocyte function.

Publications

Protection against colitis by CD100-dependent modulation of intraepithelial γδ T lymphocyte function.

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