Transient local depletion of Foxp3+ regulatory T cells during recovery from colitis via Fas/Fas ligand-induced death

Colin Reardon, Arthur Wang, Derek M. McKay

Research output: Contribution to journalArticlepeer-review

34 Scopus citations

Abstract

Regulatory T cells (Tregs) play a fundamental role in regulating the immune system in health and disease. Considerable evidence exists demonstrating that transfer of Tregs can cure colitis and a variety of other inflammatory disorders. However, little is known about the effects of inflammation on resident Tregs. Mice (BALB/c or C57BL/6) treated with an intrarectal instillation of the haptenizing agent 2,4-dinitrobenzene sulfonic acid (DNBS) develop an acute inflammatory disease, the histopathology of which peaks at 3 days posttreatment and resolves spontaneously thereafter. In this study we demonstrate that DNBS (or oxazolone)-induced colitis causes a depletion of colonic Foxp3+ Tregs 8 days posttreatment, while the proportion of Foxp3+ cells in the ileum, mesenteric lymph nodes, and spleen remains unchanged. Replenishment of the colonic T regs population was associated with the reappearance of mucosal homing (α4β7+) CD4 +Foxp3+ Tregs. Assessing the mechanism of local Tregs depletion, we found no evidence to implicate cytokine-induced phenotypic switching in the Foxp3+ population or increased SMAD7 expression despite the essential role that TGF-β has in Foxp3+ Tregs biology. Increased Fas ligand (FasL) expression was observed in the colon of colitic mice and in vitro stimulation with a Fas cross-linking Ab resulted in apoptosis of CD4+Foxp3+ but not CD4 +Foxp3- cells. Furthermore, DNBS-induced colitis in Fas/FasL-deficient mice did not result in depletion of colonic Tregs. Finally, adoptively transferred synergic Fas-/- but not Fas +/+ Tregs were protected from depletion in the colon 8 days post-DNBS treatment, thus substantiating the hypothesis that inflammation-induced local depletion of Foxp3+Tregs. in the colon of mice occurs via Fas/FasL-mediated death.

Original languageEnglish (US)
Pages (from-to)8316-8326
Number of pages11
JournalJournal of Immunology
Volume180
Issue number12
StatePublished - 2008
Externally publishedYes

ASJC Scopus subject areas

  • Immunology

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