Cutting edge: a critical role for gene silencing in preventing excessive type 1 immunity.
Immunity often depends on proper cell fate choice by helper T lymphocytes. A naive cell, with minimal expression of IFN-gamma and IL-4, must give rise to progeny expressing high levels of either one, but not both, of those cytokines to defend against protozoan and helminthic pathogens, respectively. In the present study, we show that inactivation of the Mbd2 gene, which links DNA methylation and repressed chromatin, results in enhanced resistance to the protozoan parasite Leishmania major but impaired immunity to the intestinal helminth Trichuris muris. Helper T cells from methyl CpG-binding domain protein-2-deficient mice exhibit exuberant patterns of cytokine expression despite appropriate silencing of genes encoding the lineage-specifying factors T-bet and GATA-3. These results suggest that gene silencing can facilitate the ability of a progenitor cell to give rise to appropriately differentiated daughter cells in vivo. These findings also point to novel pathways that could participate in genetic control of resistance to infection and autoimmunity.
Hutchins
Anne S
AS
Abramson Family Cancer Research Institute and Department of Medicine, University of Pennsylvania, Philadelphia, 19104, USA.
Artis
David
D
Hendrich
Brian D
BD
Bird
Adrian P
AP
Scott
Phillip
P
Reiner
Steven L
SL
D000818:Animals; D015551:Autoimmunity; D019175:DNA Methylation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology*; D020868:Gene Silencing; D020022:Genetic Predisposition to Disease; D007113:Immunity, Innate; D007371:Interferon-gamma / Q000096:biosynthesis; D018320:Leishmania major; D016773:Leishmaniasis, Cutaneous / Q000235:genetics / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000502:physiology; D014257:Trichuriasis / Q000276:immunology; D000098815:T-bet Transcription Factor
D004268:DNA-Binding Proteins; C489326:Mbd2 protein, mouse; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D014157:Transcription Factors; D007371:Interferon-gamma