Transient local depletion of Foxp3+ regulatory T cells during recovery from colitis via Fas/Fas ligand-induced death.
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 Treg population was associated with the reappearance of mucosal homing (alpha4beta7+) CD4+Foxp3+ Tregs. Assessing the mechanism of local Treg 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-beta has in Foxp3+ Treg 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.
Reardon
Colin
C
Gastrointestinal Research Group, University of Calgary, Calgary, AB, Canada.
Wang
Arthur
A
McKay
Derek M
DM
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D003092:Colitis / Q000235:genetics / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D004139:Dinitrofluorobenzene / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000276:immunology; D053222:Fas Ligand Protein / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*; D051858:Forkhead Transcription Factors / Q000096:biosynthesis; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D006241:Haptens / Q000008:administration & dosage; D007413:Intestinal Mucosa / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008817:Mice, Mutant Strains; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism / Q000473:pathology*; D013997:Time Factors; D019014:fas Receptor / Q000096:biosynthesis / Q000172:deficiency / Q000502:physiology*
D053222:Fas Ligand Protein; C491899:Fas protein, mouse; C505658:Fasl protein, mouse; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D006241:Haptens; D019014:fas Receptor; C045305:2,4-dinitrofluorobenzene sulfonic acid; D004139:Dinitrofluorobenzene