Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice

M. Y. Park, N. Srivastava, R. Sudan, D. R. Viernes, J. D. Chisholm, R. W. Engelman, W. G. Kerr

Research output: Contribution to journalArticle

16 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1429-1439
Number of pages11
JournalMucosal Immunology
Volume7
Issue number6
DOIs
StatePublished - Nov 25 2014

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Fingerprint Dive into the research topics of 'Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice'. Together they form a unique fingerprint.

  • Cite this

    Park, M. Y., Srivastava, N., Sudan, R., Viernes, D. R., Chisholm, J. D., Engelman, R. W., & Kerr, W. G. (2014). Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice. Mucosal Immunology, 7(6), 1429-1439. https://doi.org/10.1038/mi.2014.32