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Transient Local Depletion of Foxp3⁺ Regulatory T Cells during Recovery from Colitis via Fas/Fas Ligand-Induced Death¹

Gastrointestinal Research Group, University of Calgary, Calgary, Alberta, Canada

Regulatory T cells (T_regs) play a fundamental role in regulating the immune system in health and disease. Considerable evidence exists demonstrating that transfer of T_regs can cure colitis and a variety of other inflammatory disorders. However, little is known about the effects of inflammation on resident T_regs. 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⁺ T_regs 8 days posttreatment, while the proportion of Foxp3⁺ cells in the ileum, mesenteric lymph nodes, and spleen remains unchanged. Replenishment of the colonic T_reg population was associated with the reappearance of mucosal homing (₄β₇⁺) CD4⁺Foxp3⁺ T_regs. Assessing the mechanism of local T_reg 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⁺ T_reg 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 T_regs. Finally, adoptively transferred synergic Fas^–/– but not Fas^+/+ T_regs were protected from depletion in the colon 8 days post-DNBS treatment, thus substantiating the hypothesis that inflammation-induced local depletion of Foxp3⁺ T_regs in the colon of mice occurs via Fas/FasL-mediated death.

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¹ This work was supported Natural Sciences and Engineering Research Council of Canada Grant 341924. D.M.M. is supported by a Canada Research Chair (Tier 1) and an Alberta Heritage Foundation for Medical Research Scientist Award. C.R. was a recipient of a Natural Sciences and Engineering Research Council of Canada studentship.

² Address correspondence and reprint requests to Dr. Derek M. McKay, Gastrointestinal Research Group, Department of Physiology and Biophysics, HS-1877, University of Calgary, 3330 Hospital Drive Northwest, Calgary, Alberta, Canada T2N 4N1. E-mail address: dmckay{at}ucalgary.ca

³ Abbreviations used in this paper: T_reg, regulatory T cell; CMF, Ca²⁺- and Mg²⁺-free; DNBS, 2,4-dinitrobenzene sulfonic acid; EtOH, ethanol; FasL, Fas ligand; IBD, inflammatory bowel disease; i.r., intrarectal; LPL, lamina propria lymphocyte; MLN, mesenteric lymph node.