T cell subsets and environmental factors in Citrobacter rodentium infection

ABSTRACTBoth 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 pathogenCitrobacter rodentiumleads to a significant reduction in colonic goblet cell numbers (goblet cell depletion). This pathology depends on T and/or B cells, asRag1−/−mice do not suffer this depletion during infection, instead suffering high mortality rates. To address the immune mechanisms involved, we reconstitutedRag−/−mice with either CD4+or CD8+T cells. Both T cell subsets increasedRag1−/−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 thatC. rodentiumcells 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 theC. 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.

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Central Role for B Lymphocytes and CD4+ T Cells in Immunity to Infection by the Attaching and Effacing Pathogen Citrobacter rodentium

Infection and Immunity ◽

10.1128/iai.71.9.5077-5086.2003 ◽

2003 ◽

Vol 71 (9) ◽

pp. 5077-5086 ◽

Cited By ~ 121

Author(s):

Cameron P. Simmons ◽

Simon Clare ◽

Marjan Ghaem-Maghami ◽

Tania K. Uren ◽

Joanna Rankin ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cells ◽

B Lymphocytes ◽

Adoptive Transfer ◽

Acute Infection ◽

Bacterial Pathogen ◽

T Cell Subsets ◽

Citrobacter Rodentium ◽

Severe Colitis

ABSTRACT Citrobacter rodentium, an attaching-effacing bacterial pathogen, establishes an acute infection of the murine colonic epithelium and induces a mild colitis in immunocompetent mice. This study describes the role of T-cell subsets and B lymphocytes in immunity to C. rodentium. C57Bl/6 mice orally infected with C. rodentium resolved infection within 3 to 4 weeks. Conversely, systemic and colonic tissues of RAG1−/− mice orally infected with C. rodentium contained high and sustained pathogen loads, and in the colon this resulted in a severe colitis. C57Bl/6 mice depleted of CD4+ T cells, but not CD8+ T cells, were highly susceptible to infection and also developed severe colitis. Mice depleted of CD4+ T cells also had diminished immunoglobulin G (IgG) and IgA antibody responses to two C. rodentium virulence-associated determinants, i.e., EspA and intimin, despite having a massively increased pathogen burden. Mice with an intact T-cell compartment, but lacking B cells (μMT mice), were highly susceptible to C. rodentium infection. Systemic immunity, but not mucosal immunity, could be restored by adoptive transfer of convalescent immune sera to infected μMT mice. Adoptive transfer of immune B cells, but not naïve B cells, provided highly variable immunity to recipient μMT mice. The results suggest that B-cell-mediated immune responses are central to resolution of a C. rodentium infection but that the mechanism through which this occurs requires further investigation. These data are relevant to understanding immunity to enteric attaching and effacing bacterial pathogens of humans.

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