Nature Immunology
5, 1251 - 1259 (2004)
Published online: 31 October 2004; | doi:10.1038/ni1135
Deletion of a conserved Il4 silencer impairs T helper type 1−mediated immunityK Mark Ansel1, 2, Rebecca J Greenwald1, 3, Suneet Agarwal1, 2, Craig H Bassing2, 4, Silvia Monticelli1, 2, 5, Jeneen Interlandi2, Ivana M Djuretic1, 2, Dong U Lee1, 2, Arlene H Sharpe1, 3, Frederick W Alt2, 4, 6
& Anjana Rao1, 21
Department of Pathology, Harvard Medical School, Boston, Massachusetts 02115, USA. 2
CBR Institute for Biomedical Research, Boston, Massachusetts 02115, USA. 3
Department of Pathology, Brigham and Women's Hospital, Boston, Massachusetts 02115, USA. 4
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA. 5
Division of Biotechnologies applied to Medical Sciences, University of Milan, 20133 Milan, Italy. 6
Howard Hughes Medical Institute and the Children's Hospital, Boston, Massachusetts 02115, USA.
Correspondence should be addressed to Anjana Rao arao@cbr.med.harvard.eduHelper 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- also produced abundant interleukin 4 in vitro and in vivo. Despite mounting a vigorous interferon- 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.
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