| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
* Clinical Immunology Group and
Cell Biology Group, Deutsches Rheuma-Forschungszentrum Berlin, Berlin, Germany;
EPIGENOMICS, Berlin, Germany;
Department of Rheumatology, Charité Campus Mitte, Berlin, Germany; and
¶ Center of Research, Transfer, High Education MCIDNENT, University of Florence, Firenze, Italy
Epigenetic modifications, including DNA methylation, profoundly influence gene expression of CD4+ Th-specific cells thereby shaping memory Th cell function. We demonstrate here a correlation between a lacking fixed potential of human memory Th cells to re-express the immunoregulatory cytokine gene IL10 and its DNA methylation status. Memory Th cells secreting IL-10 or IFN-
were directly isolated ex vivo from peripheral blood of healthy volunteers, and the DNA methylation status of IL10 and IFNG was assessed. Limited difference in methylation was found for the IL10 gene locus in IL-10-secreting Th cells, as compared with Th cells not secreting IL-10 isolated directly ex vivo or from in vitro-established human Th1 and Th2 clones. In contrast, in IFN-+ memory Th cells the promoter of the IFNG gene was hypomethylated, as compared with IFN--nonsecreting memory Th cells. In accordance with the lack of epigenetic memory, almost 90% of ex vivo-isolated IL-10-secreting Th cells lacked a functional memory for IL-10 re-expression after restimulation. Our data indicate that IL10 does not become epigenetically marked in human memory Th cells unlike effector cytokine genes such as IFNG. The exclusion of IL-10, but not effector cytokines, from the functional memory of human CD4+ T lymphocytes ex vivo may reflect the need for appropriate regulation of IL-10 secretion, due to its potent immunoregulatory potential.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by grants from the Deutsche Forschungsgemeinschaft (TH 806/1-1, SFB421 TP B6, SFB 650 TP 11, and BMBF 312102).
2 J.D. and C.I. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Andreas Thiel and Dr. Jun Dong, Clinical Immunology, Deutsches Rheuma-Forschungszentrum Berlin, Charitéplatz 1, Berlin, Germany. E-mail addresses: thiel@drfz.de and dong{at}drfz.de
4 Abbreviations used in this paper: Tr1, T regulatory type 1 cell; P/I, PMA/ionomycin; HSS, hypersensitivity site; ChIP, chromatin immunoprecipitation; H3Ac, histone 3 acetylation; H3K4me3, histone 3 lysine 4 trimethylation; ROI, regions of interest; Dnmt, DNA methyltransferase.
This article has been cited by other articles:
|
|
 |
|
  K. K. McKinstry, T. M. Strutt, A. Buck, J. D. Curtis, J. P. Dibble, G. Huston, M. Tighe, H. Hamada, S. Sell, R. W. Dutton, et al. IL-10 Deficiency Unleashes an Influenza-Specific Th17 Response and Enhances Survival against High-Dose Challenge J. Immunol., June 15, 2009; 182(12): 7353 - 7363. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Tsuji-Takayama, M. Suzuki, M. Yamamoto, A. Harashima, A. Okochi, T. Otani, T. Inoue, A. Sugimoto, T. Toraya, M. Takeuchi, et al. The Production of IL-10 by Human Regulatory T Cells Is Enhanced by IL-2 through a STAT5-Responsive Intronic Enhancer in the IL-10 Locus J. Immunol., September 15, 2008; 181(6): 3897 - 3905. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
