Loss of methylation at the IFNG promoter and CNS-1 is associated with the development of functional IFN-γ memory in human CD4+ T lymphocytes



This article is corrected by:

  1. Errata: Correction Volume 44, Issue 10, 3144, Article first published online: 13 October 2014

Full correspondence: Dr. Jun Dong, Cell Biology Group, German Rheumatism Research Centre Berlin 1, 10117, Berlin, Germany

Fax: +49-30-28460603

e-mail: dong@drfz.de

Additional correspondence: Prof. Dr. Andreas Thiel, Regenerative Immunology and Aging, Berlin-Brandenburg Center for Regenerative Therapies, Charité, Campus Virchow-Klinikum Augustenburger Platz 1, 13353, Berlin, Germany

Fax: +49-30-450539955

e-mail: andreas.thiel@charite.de


Cytokine memory for IFN-γ production by effector/memory Th1 cells plays a key role in both protective and pathological immune responses. To understand the epigenetic mechanism determining the ontogeny of effector/memory Th1 cells characterized by stable effector functions, we identified a T-cell-specific methylation pattern at the IFNG promoter and CNS-1 in ex vivo effector/memory Th1 cells, and investigated methylation dynamics of these regions during the development of effector/memory Th1 cells. During Th1 differentiation, demethylation occurred at both the promoter and CNS-1 regions of IFNG as early as 16 h, and this process was independent of cell proliferation and DNA synthesis. Using an IFN-γ capture assay, we found early IFN-γ-producing cells from 2-day differentiating cultures acquired “permissive” levels of demethylation and developed into effector/memory Th1 cells undergoing progressive demethylation at the IFNG promoter and CNS-1 when induced by IL-12. Methylation levels of these regions in effector/memory Th1 cells of peripheral blood from rheumatoid arthritis patients correlated inversely with reduced frequencies of IFN-γ-producers, coincident with recruitment of effector/memory Th1 cells to the site of inflammation. Thus, after termination of TCR stimulation, IL-12 signaling potentiates the stable functional IFN-γ memory in effector/memory Th1 cells characterized by hypomethylation at the IFNG promoter and CNS-1.