title: Foxp3 transcription factor is proapoptotic and lethal to developing regulatory T cells unless counterbalanced by cytokine survival signals.
abstract: Immune tolerance requires regulatory T (Treg) cells to prevent autoimmune disease, with the transcription factor Foxp3 functioning as the critical regulator of Treg cell development and function. We report here that Foxp3 was lethal to developing Treg cells in the thymus because it induced a unique proapoptotic protein signature (Puma⁺⁺⁺p-Bim⁺⁺p-JNK⁺⁺DUSP6⁻) and repressed expression of prosurvival Bcl-2 molecules. However, Foxp3 lethality was prevented by common gamma chain (γc)-dependent cytokine signals that were present in the thymus in limiting amounts sufficient to support only ∼1 million Treg cells. Consequently, most newly arising Treg cells in the thymus were deprived of this signal and underwent Foxp3-induced death, with Foxp3⁺CD25⁻ Treg precursor cells being the most susceptible. Thus, we identify Foxp3 as a proapoptotic protein that requires developing Treg cells to compete with one another for limiting amounts of γc-dependent survival signals in the thymus.
authors.affiliation: Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
authors.forename: Xuguang
authors.initials: X
authors.lastname: Tai
authors.forename: Batu
authors.initials: B
authors.lastname: Erman
authors.forename: Amala
authors.initials: A
authors.lastname: Alag
authors.forename: Jie
authors.initials: J
authors.lastname: Mu
authors.forename: Motoko
authors.initials: M
authors.lastname: Kimura
authors.forename: Gil
authors.initials: G
authors.lastname: Katz
authors.forename: Terry
authors.initials: T
authors.lastname: Guinter
authors.forename: Tom
authors.initials: T
authors.lastname: McCaughtry
authors.forename: Ruth
authors.initials: R
authors.lastname: Etzensperger
authors.forename: Lionel
authors.initials: L
authors.lastname: Feigenbaum
authors.forename: Dinah S
authors.initials: DS
authors.lastname: Singer
authors.forename: Alfred
authors.initials: A
authors.lastname: Singer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism*; D000072224:Bcl-2-Like Protein 11; D002470:Cell Survival; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology*; D054642:Dual Specificity Phosphatase 6 / Q000235:genetics / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D053631:Interleukin Receptor Common gamma Subunit / Q000276:immunology*; D038041:Lymphopoiesis / Q000235:genetics; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D016207:Cytokines; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D053631:Interleukin Receptor Common gamma Subunit; D008565:Membrane Proteins; C488588:PUMA protein, mouse; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D025521:Tumor Suppressor Proteins; D048670:MAP Kinase Kinase 4; D054642:Dual Specificity Phosphatase 6; C517036:Dusp6 protein, mouse