IL-10 Is Excluded from the Functional Cytokine Memory of Human CD4+ Memory T Lymphocytes

Abstract

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-γ 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-γ+ memory Th cells the promoter of the IFNG gene was hypomethylated, as compared with IFN-γ-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.

IFN-α and CD46 stimulation are associated with active lupus and skew natural T regulatory cell differentiation to type 1 regulatory T (Tr1) cells

“…This suggests that Tr1 cells are not a separate T-cell lineage commitment, but represent, during inflammation-triggered adaptive immunity, a stage of functional differentiation in the life cycle of immune-stimulated T cells originating from most, if not all, T-cell subtypes. This paradigm is supported by Tr1 characteristics: (i) their origin from a broad range of Ag-stimulated T cells (8), (ii) their absence of associated specific phenotypic markers (28), and (iii) their lack of epigenetic functional memory as assessed by DNA status (29). The context-dependent dual regulatory activities of nTregs should highlight the mechanisms triggering their dysfunction in autoimmune diseases.…”

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

“…The Journal of ImmunologyIFNG, IL17A, and IL17F gene loci (Table I), selected on the basis of evolutionary conservation among species and CpG site density in noncoding sequences (promoter and CNS) (24), in Th17, Th17/ Th1, classic Th1, and nonclassic Th1 (Th17 derived), clones (Figs. 1, 2).…”

Identification of Noncytotoxic and IL-10–Producing CD8+AT2R+ T Cell Population in Response to Ischemic Heart Injury

“…Later, convergent evidence suggests that CD8 + T cells can be differentiated into several subsets. Based on the pattern of cytokine production, the regulatory T cell subsets have been not only described in CD4 + T cells (20) but identified in CD8 + T cells (14,15). These CD8 + regulatory T cells, which are characterized by the production of immune suppressive cytokines involving mainly IL-10, have been generated from native CD8 + T cells in peripheral blood of healthy Intramyocardial transplantation of CD8 + AT2R + T cells led to a reduced infarct size in recipients rats after MI.…”