Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice.
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.
Dept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA.
M Y
MY
Park
Dept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA.
N
N
Srivastava
Dept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA.
R
R
Sudan
Department of Chemistry, Syracuse University, Syracuse, NY, USA.
D R
DR
Viernes
Department of Chemistry, Syracuse University, Syracuse, NY, USA.
J D
JD
Chisholm
Depts. of Pathology & Cell Biology, and Pediatrics, H. Lee Moffitt Comprehensive Cancer Center & Research Institute, University of South Florida, Tampa, FL, USA.
R W
RW
Engelman
Dept. of Microbiology & Immunology, SUNY Upstate Medical University, Syracuse, NY, USA.|Department of Chemistry, Syracuse University, Syracuse, NY, USA.|Dept. of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA.
W G
WG
Kerr
D000818:Animals; D053181:Caspase 8 / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D003424:Crohn Disease / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology; D000072181:Inositol Polyphosphate 5-Phosphatases; D007413:Intestinal Mucosa / Q000276:immunology* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000276:immunology*; D011014:Pneumonia / Q000235:genetics / Q000276:immunology*; D020545:Respiratory Mucosa / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D019014:fas Receptor / Q000235:genetics / Q000276:immunology
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D019014:fas Receptor; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; C505526:Casp8 protein, mouse; D053181:Caspase 8