Demethylation of the RORC2 and IL17A in Human CD4(+) T Lymphocytes Defines Th17 Origin of Nonclassic Th1 Cells

作者：Mazzoni Alessio; Santarlasci Veronica; Maggi Laura; Capone Manuela; Rossi Maria Caterina; Querci Valentina; De Palma Raffaele; Chang Hyun Dong; Thiel Andreas; Cimaz Rolando; Liotta Francesco; Cosmi Lorenzo; Maggi Enrico; Radbruch Andreas; Romagnani Sergio; Dong Jun; Annunziato Francesco^*

来源：The Journal of Immunology, 2015, 194(7): 3116-3126.

DOI：10.4049/jimmunol.1401303

Th17-derived Th1 lymphocytes, termed nonclassic, differ from classic Th1 cells because of the presence of retinoic acid orphan receptor (ROR)C2 and the surface expression of CD161 and CCR6. We demonstrate in this article that nonclassic Th1 cells, like Th17 cells, have a marked RORC2 and IL17A demethylation, whereas classic Th1 cells exhibit a complete methylation of these genes. The analysis of RORC2 DNA methylation in the CD4(+) CD161(+) and CD4(+) CD161(-) naive Th subsets from umbilical cord blood surprisingly revealed comparable hypermethylation levels. PCR analysis at the single-cell level revealed that RORC2 mRNA was expressed by none of the CD4(+) CD161(-) and present only in a minority of CD4(+) CD161(+) naive Th cells. These findings provide two important novel observations on the physiology of human Th17 cells: 1) they confirm at the epigenetic level the origin of nonclassic Th1 cells from Th17 cells, also identifying in the RORC2 and IL17A methylation status a novel tool for their distinction from classic Th1 cells, and 2) they demonstrate that RORC2-expressing cells are only a minority in the subset of CD4+ CD161+ naive Th cells, which are known to contain all Th17 cell precursors.

• 出版日期2015-4-1