title: Foxp3-mediated suppression of CD95L expression confers resistance to activation-induced cell death in regulatory T cells.
abstract: CD4(+)CD25(++)Foxp3(+) regulatory T cells (Tregs) control self-reactive cells to maintain peripheral tolerance. Treg homeostasis has to be controlled tightly to ensure balanced Treg-mediated suppression. One mechanism that regulates the CD4(+) T cell pool is activation-induced cell death (AICD). This is mimicked in vitro by TCR restimulation-induced expression of the death ligand CD95L (FasL/APO-1L/CD178) in expanded T cells. These cells express the death receptor CD95 (Fas/APO-1), and binding of CD95L to CD95 results in AICD. In contrast, Tregs do not undergo AICD upon TCR (re)stimulation in vitro despite a functional CD95 cell death pathway. In this study, we show that human and murine Tregs express low levels of CD95L upon stimulation. Knockdown of the transcriptional repressor Foxp3 partially rescues CD95L expression and AICD in human Tregs. Moreover, upon stimulation Foxp3-mutant Tregs from Scurfy mice express CD95L similar to conventional T cells. We further addressed whether exogenous CD95 stimulation provides a mechanism of Treg homeostatic control in vivo in mice. Triggering of CD95 reduced Treg numbers systemically as reflected by in vivo imaging and decreased GFP(+) Treg numbers ex vivo. Our study reveals that Foxp3 negatively regulates CD95L expression in Tregs and demonstrates that Tregs are susceptible to homeostatic control by CD95 stimulation.
authors: Division of Immunogenetics, German Cancer Research Center, Heidelberg 69120, Germany.
authors: Eva-Maria
authors: EM
authors: Weiss
authors: Angelika
authors: A
authors: Schmidt
authors: Diana
authors: D
authors: Vobis
authors: Natalio
authors: N
authors: Garbi
authors: Katharina
authors: K
authors: Lahl
authors: Christian T
authors: CT
authors: Mayer
authors: Tim
authors: T
authors: Sparwasser
authors: Andreas
authors: A
authors: Ludwig
authors: Elisabeth
authors: E
authors: Suri-Payer
authors: Nina
authors: N
authors: Oberle
authors: Peter H
authors: PH
authors: Krammer
mesh_terms: D000818:Animals; D016923:Cell Death / Q000235:genetics / Q000276:immunology; D053222:Fas Ligand Protein / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism
chemical_list: C418974:FOXP3 protein, human; D053222:Fas Ligand Protein; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D011948:Receptors, Antigen, T-Cell