The development of IL-17/IFN-γ-double producing CTLs from Tc17 cells is driven by epigenetic suppression of Socs3 gene promoter.
The plasticity of T lymphocytes induced by epigenetic modifications of gene promoters may play a pivotal role in controlling their effector functions, which are sometimes causally associated with immune disorders. IL -17-producing T cells, which induce type 17 immune responses, are newly identified pathogenic effector cells. The type 1 signature cytokine IFN-γ strongly inhibits their differentiation, indicating a mutually exclusive relationship between type 17- and type 1-immune responses. However, many reports indicate the presence of a unique IL-17/IFN-γ-double producing T-cell subset in various inflammatory settings, although the mechanisms responsible for their development and their precise functions remain unclear. Here, we demonstrate that IL-12 permits the conversion of mouse IL-17-producing CD8(+)  T (Tc17) cells to IL-17/IFN-γ-double producing CD8(+)  T (Tc17/IFN-γ) cells, and that this conversion is due to repressive epigenetic modifications of Socs3 gene promoters. Moreover, we show that SOCS3 strongly regulates the capability of Tc17 cells to produce IL-17, in addition to regulating the expression of the type 17-master regulator RORγt. These findings elucidate the mechanisms underlying the conversion of Tc17 cells into Tc17/IFN-γ cells. As these cells are known to have potent antitumor activities, manipulation of these conversion mechanisms for therapeutic tumor immunity may be possible.
Division of ROYCE' Health Bioscience, Section of Disease Control, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.
Takayuki
T
Satoh
Masaki
M
Tajima
Daiko
D
Wakita
Hidemitsu
H
Kitamura
Takashi
T
Nishimura
D000818:Animals; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D057890:Epigenomics / Q000379:methods; D007167:Immunotherapy / Q000379:methods; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics* / Q000276:immunology; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000172:deficiency / Q000235:genetics* / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000276:immunology
D020381:Interleukin-17; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; C491411:Socs3 protein, mouse; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D018664:Interleukin-12; D007371:Interferon-gamma