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Background

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).

Methods

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.

Results

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.

Conclusions

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.

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Copyright © 2013 Crohn's & Colitis Foundation of America, Inc.
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