CD4+ T cells drive goblet cell depletion during Citrobacter rodentium infection

Infect Immun. 2013 Dec;81(12):4649-58. doi: 10.1128/IAI.00655-13. Epub 2013 Oct 7.

Abstract

Both idiopathic and infectious forms of colitis disrupt normal intestinal epithelial cell (IEC) proliferation and differentiation, although the mechanisms involved remain unclear. Recently, we demonstrated that infection by the attaching and effacing murine pathogen Citrobacter rodentium leads to a significant reduction in colonic goblet cell numbers (goblet cell depletion). This pathology depends on T and/or B cells, as Rag1(-/-) mice do not suffer this depletion during infection, instead suffering high mortality rates. To address the immune mechanisms involved, we reconstituted Rag(-/-) mice with either CD4(+) or CD8(+) T cells. Both T cell subsets increased Rag1(-/-) mouse survival during infection, with mice that received CD8(+) T cells developing colonic ulcers but not goblet cell depletion. In contrast, mice that received CD4(+) T cells showed goblet cell depletion in concert with exaggerated IEC proliferation. To define the possible involvement of T cell-derived cytokines, we infected gamma interferon receptor gene knockout (IFN-γR(-/-)) mice and wild-type mice given interleukin 17A (IL-17A) neutralizing antibodies and found that IFN-γ signaling was required for both goblet cell depletion and increased IEC proliferation. Immunostaining revealed that C. rodentium cells preferentially localized to nonhyperplastic crypts containing numerous goblet cells, whereas hyperplastic, goblet cell-depleted crypts appeared protected from infection. To address whether goblet cell depletion benefits the C. rodentium-infected host, we increased goblet cell numbers using the γ-secretase inhibitor dibenzazepine (DBZ), which resulted in greatly increased pathogen burdens and mortality rates. These results demonstrate that goblet cell depletion reflects host immunomodulation of IEC homeostasis and reflects a novel host defense mechanism against mucosal-adherent pathogens.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyloid Precursor Protein Secretases / antagonists & inhibitors
  • Animals
  • Antibodies, Bacterial / immunology*
  • Antibodies, Neutralizing / immunology
  • B-Lymphocytes / immunology
  • Bacterial Load / drug effects
  • CD4-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / immunology*
  • Cell Differentiation
  • Cell Proliferation
  • Citrobacter rodentium / immunology
  • Colitis / immunology
  • Colitis / microbiology
  • Colitis / mortality
  • Dibenzazepines
  • Enterobacteriaceae Infections / immunology*
  • Enterobacteriaceae Infections / mortality
  • Epithelial Cells / immunology
  • Epithelial Cells / metabolism
  • Goblet Cells / metabolism*
  • Interferon-gamma / genetics
  • Interferon-gamma / metabolism
  • Interleukin-17 / immunology
  • Intestinal Mucosa / immunology
  • Intestinal Mucosa / microbiology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Signal Transduction / immunology

Substances

  • Antibodies, Bacterial
  • Antibodies, Neutralizing
  • Dibenzazepines
  • Interleukin-17
  • Interferon-gamma
  • Amyloid Precursor Protein Secretases
  • dibenzazepine