Epithelial cell specific Raptor is required for initiation of type 2 mucosal immunity in small intestine

Sci Rep. 2017 Jul 17;7(1):5580. doi: 10.1038/s41598-017-06070-w.

Abstract

Intestinal tuft cells are one of 4 secretory cell linages in the small intestine and the source of IL-25, a critical initiator of the type 2 immune response to parasite infection. When Raptor, a critical scaffold protein for mammalian target of rapamycin complex 1 (mTORC1), was acutely deleted in intestinal epithelium via Tamoxifen injection in Tritrichomonas muris (Tm) infected mice, tuft cells, IL-25 in epithelium and IL-13 in the mesenchyme were significantly reduced, but Tm burden was not affected. When Tm infected mice were treated with rapamycin, DCLK1 and IL-25 expression in enterocytes and IL-13 expression in mesenchyme were diminished. After massive small bowel resection, tuft cells and Tm were diminished due to the diet used postoperatively. The elimination of Tm and subsequent re-infection of mice with Tm led to type 2 immune response only in WT, but Tm colonization in both WT and Raptor deficient mice. When intestinal organoids were stimulated with IL-4, tuft cells and IL-25 were induced in both WT and Raptor deficient organoids. In summary, our study reveals that enterocyte specific Raptor is required for initiating a type 2 immune response which appears to function through the regulation of mTORC1 activity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Doublecortin-Like Kinases
  • Down-Regulation
  • Enterocytes / cytology*
  • Enterocytes / metabolism
  • Epithelial Cells / cytology
  • Epithelial Cells / metabolism
  • Immunity, Mucosal / drug effects
  • Interleukin-13 / genetics
  • Interleukin-13 / metabolism
  • Interleukins / genetics
  • Interleukins / metabolism
  • Intestine, Small / cytology*
  • Intestine, Small / metabolism
  • Mechanistic Target of Rapamycin Complex 1 / metabolism
  • Mice
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Protozoan Infections, Animal / drug therapy
  • Protozoan Infections, Animal / immunology*
  • Regulatory-Associated Protein of mTOR / deficiency*
  • Sirolimus / administration & dosage*
  • Sirolimus / pharmacology
  • Tamoxifen / administration & dosage
  • Tamoxifen / pharmacology
  • Tritrichomonas / immunology*

Substances

  • Interleukin-13
  • Interleukins
  • Mydgf protein, mouse
  • Regulatory-Associated Protein of mTOR
  • Rptor protein, mouse
  • Tamoxifen
  • Doublecortin-Like Kinases
  • Dclk1 protein, mouse
  • Mechanistic Target of Rapamycin Complex 1
  • Protein Serine-Threonine Kinases
  • Sirolimus