Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice
| Autor: | John D. Chisholm, Robert W. Engelman, William G. Kerr, Neetu Srivastava, Mi Young Park, Raki Sudan, Dennis R. Viernes |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Programmed cell death
ileitis Fas Ligand Protein Myeloid Cell Survival T-Lymphocytes T cell Immunology T cells Respiratory Mucosa Biology Caspase 8 Article Fas ligand SHIP1 inhibitor Mice 03 medical and health sciences 0302 clinical medicine caspase 8 Crohn Disease medicine pneumonia Animals Immunology and Allergy fas Receptor Intestinal Mucosa 030304 developmental biology Mice Knockout 0303 health sciences Innate immune system Inositol Polyphosphate 5-Phosphatases apoptosis Fas receptor SHIP1 Phosphoric Monoester Hydrolases 3. Good health Crohn's disease adoptive T cell transfer (ACT) medicine.anatomical_structure Phosphatidylinositol-3 4 5-Trisphosphate 5-Phosphatases 3-α-aminocholestane (3AC) CD8 030215 immunology |
| Zdroj: | Mucosal immunology |
| ISSN: | 1933-0219 |
| DOI: | 10.1038/mi.2014.32 |
| Popis: | T cells have a critical role in immune surveillance at mucosal surfaces. SHIP1(-/-) mice succumb to mucosal inflammatory disease that afflicts the lung and small intestine (SI). The basis of this condition has not been defined. Here we show that SHIP1 is required for the normal persistence and survival of T cells in mucosal tissues. We find that CD4 and CD8 effector T cells are reduced; however, Treg cells are increased in the SI and lungs of SHIP1(-/-) and CD4CreSHIP(flox/flox) mice. Furthermore, a subset of T cells in the SI of SHIP1(-/-) mice are FasL(+) and are more susceptible to extrinsic cell death. Mechanistic analyses showed that SHIP1 associates with the death receptor CD95/Fas and treatment with a Caspase 8 inhibitor prevents SHIP1 inhibitor-mediated T-cell death. Notably, mucosal inflammation in SHIP1(-/-) mice is reduced by treatment with a Caspase 8 inhibitor. We also find that the incidence of Crohn's disease (CD) and pneumonia is significantly increased in mice with dual T and myeloid lineage SHIP1 deletion but not in single lineage-deleted mice. Thus, by promoting survival of protective T cells, thereby preventing an inflammatory myeloid response, SHIP1 maintains an appropriate balance of innate immune function at mucosal surfaces necessary for immune homeostasis. |
| Databáze: | OpenAIRE |
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