Deletion of a conserved Il4 silencer impairs T helper type 1-mediated immunity.
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.
Ansel
K Mark
KM
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA.
Greenwald
Rebecca J
RJ
Agarwal
Suneet
S
Bassing
Craig H
CH
Monticelli
Silvia
S
Interlandi
Jeneen
J
Djuretic
Ivana M
IM
Lee
Dong U
DU
Sharpe
Arlene H
AH
Alt
Frederick W
FW
Rao
Anjana
A
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
D002843:Chromatin; D016207:Cytokines; D015847:Interleukin-4; D003850:Deoxyribonuclease I