P-188 SHIP1 Prevents Mucosal Inflammation by Protecting T Cells from Extrinsic Cell Deathстатья из журнала
Аннотация: T cells play a critical role in immune surveillance at mucosal surfaces. SHIP1−/− mice are known to succumb to profound mucosal inflammatory disease that afflicts the lung. We recently showed that SHIP1−/− mice suffer from a severe and spontaneous form of Crohn's like ileitis. SHIP1−/− mice show a significant reduction in both CD4 and CD8 T cells in the small intestine leading us to hypothesize that their disease results from selective T cell deficiency at these sites that culminates in an over-response by SHIP1−/− neutrophils and other inflammatory myeloid cells leading to tissue destruction.(Kerr et al GUT 2011 PMCID: 3022365). Adoptive transfer of WT T cells into SHIP−/− mice followed by analysis of survival and histopathology in the small intestine and lungs. In vivo competition assays of WT and SHIP1−/− T cells in blood, spleen, small intestine and lungs. Treatment of SHIP1−/− mice with a Caspase 8 inhibitor followed by analysis of T cell recovery in the small intestine and lungs. FACS quantitation of T cell subsets and their expression of FAsL in the lungs and small intestine of WT and SHIP1−/− mice. Treatment of a human T cell line with SHIP1 inhibitor to induce apoptosis and rescue by pre-treatment with a Caspase 8 inhibitor. Biochemical analysis of Fas-SHIP1 association by immunoprecipitation and Western blot. We will show the following: (1) A SHIP1+/+ T cell graft protects SHIP1−/− mice from lethal mucosal inflammation (2) SHIP1 is required for the survival of T cells in the gut and lungs. (3) SHIP1−/− mucosal T cells are more susceptible to Caspase 8 mediated cell death (4) SHIP1 prevents inappropriate induction of FasL on lamina propria T cells. (5) Caspase 8 inhibition protects human T cells from SHIP1 inhibitor induced apoptosis. Here we show that the life-threatening mucosal inflammation in SHIP1−/− mice is prevented by reconstitution with a SHIP1-competent T cell graft. Moreover, we find that the persistence of CD4+ and CD8+ T cells in the lungs, and CD4+ T cells in the small intestine, require expression of SHIP1 due to its protection of mucosal T cells from Caspase 8 mediated extrinsic cell death. Thus, SHIP1 maintains the balance of adaptive and innate immune functions at mucosal surfaces necessary for immune homeostasis. In forms of IBD where SHIP1 is found to be deficient, SHIP1 agonists may provide a therapeutic option. Our findings also suggest that SHIP1 inhibitors could be used to selectively deplete autoreactive T cells in forms of IBD where SHIP1 is not found to be deficient.
Год издания: 2013
Авторы: William G. Kerr, Mi Young Park, Raki Sudan, Dennis R. Viernes, John D. Chisholm, Robert W. Engelman, Neetu Srivastava
Издательство: Oxford University Press
Источник: Inflammatory Bowel Diseases
Ключевые слова: Helicobacter pylori-related gastroenterology studies, Protein Tyrosine Phosphatases, Immune Cell Function and Interaction
Открытый доступ: closed
Том: 19
Страницы: S100–S101