title: Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity.
abstract: Helper T cell differentiation involves silencing as well as activation of gene expression. We have identified a conserved silencer of the gene encoding interleukin 4 (Il4) marked by DNase I hypersensitivity (HS IV) and permissive chromatin structure in all helper T cells. Deletion of HS IV increased Il4 and Il13 transcription by naive T cells and led to T helper type 2 skewing in vitro. HS IV controlled Il4 silencing during T helper type 1 differentiation, as HS IV-deficient T helper type 1 cells that expressed interferon-gamma also produced abundant interleukin 4 in vitro and in vivo. Despite mounting a vigorous interferon-gamma response, HS IV-deficient mice were more susceptible to Leishmania major infection than were wild-type littermate control mice, showing a critical function for Il4 silencing in T helper type 1-mediated immunity.
authors.affiliation: Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
authors.forename: K Mark
authors.initials: KM
authors.lastname: Ansel
authors.forename: Rebecca J
authors.initials: RJ
authors.lastname: Greenwald
authors.forename: Suneet
authors.initials: S
authors.lastname: Agarwal
authors.forename: Craig H
authors.initials: CH
authors.lastname: Bassing
authors.forename: Silvia
authors.initials: S
authors.lastname: Monticelli
authors.forename: Jeneen
authors.initials: J
authors.lastname: Interlandi
authors.forename: Ivana M
authors.initials: IM
authors.lastname: Djuretic
authors.forename: Dong U
authors.initials: DU
authors.lastname: Lee
authors.forename: Arlene H
authors.initials: AH
authors.lastname: Sharpe
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Anjana
authors.initials: A
authors.lastname: Rao
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D002478:Cells, Cultured; D002843:Chromatin / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics*; D016207:Cytokines / Q000172:deficiency / Q000235:genetics; D003850:Deoxyribonuclease I / Q000378:metabolism; D005786:Gene Expression Regulation; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D015847:Interleukin-4 / Q000235:genetics* / Q000276:immunology*; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000276:immunology; D051379:Mice; D018345:Mice, Knockout; D012045:Regulatory Sequences, Nucleic Acid / Q000235:genetics*; D017384:Sequence Deletion / Q000235:genetics*; D018417:Th1 Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D018418:Th2 Cells / Q000166:cytology / Q000276:immunology / Q000378:metabolism
chemical_list: D002843:Chromatin; D016207:Cytokines; D015847:Interleukin-4; D003850:Deoxyribonuclease I