Epigenetic modification of the human CCR6 gene is associated with stable CCR6 expression in T cells

Abstract

CCR6 is a chemokine receptor expressed on Th17 cells and regulatory T cells that is induced by T-cell IntroductionSpecific patterns of chemokine receptor expression ensure an orchestrated migration of leukocytes throughout the body, where immune cells home to their target tissues under both steady-state and inflammatory conditions. The chemokine receptor CCR6 is widely expressed on human blood and tissue leukocytes, including subsets of dendritic cells, CD45RO ϩ effector/memory T cells, CD25 high regulatory T cells (Tregs), naive and memory B cells, NKT cells, and NK cells. [1][2][3][4][5][6] On memory T cells, CCR6 is expressed on a population of autoreactive interleukin-10 (IL-10)-producing cells 7 and subsets of skin-and mucosa-homing cells. Several studies have further shown that CCR6 is consistently expressed on inflammatory IL-17-producing CD4 ϩ T cells, [8][9][10] which are involved in a wide array of adverse inflammatory diseases, such as rheumatoid arthritis, psoriatic disease, inflammatory bowel disease, or encephalopathies in mice and humans. [10][11][12][13][14] More recently, CCR6 was identified as a new risk factor for rheumatoid arthritis; moreover, a nucleotide polymorphism within the CCR6 locus was shown to be associated with susceptibility to rheumatoid arthritis, Graves disease, and Crohn disease. 15,16 CCR6 was shown to play a pivotal role in directing inflammatory and regulatory cells to inflamed tissues or the gut, where the ligand of CCR6 CCL20 is expressed. 13,17,18 Although most chemokine-chemokine receptor interactions are characterized by a high promiscuity, CCR6 binds only CCL20 and ␤-defensins. 1It is widely assumed that the differentiation of T cells into specialized memory subsets also involves the acquisition and stable expression of homing-and chemokine receptor repertoires, allowing tissue-or inflammation-specific trafficking of these subsets. 19 Evidence has been provided in recent years that differentiation of T cells into distinct lineages with stable phenotypes and functions involves epigenetic regulation of critical effector molecules [20][21][22] or lineage-specific transcription factors, such as Foxp3 in Tregs. [23][24][25][26] Only few studies demonstrated that molecules involved in trafficking are subject to epigenetic regulation in T cells 27,28 or cancer cells. 29,30 In addition, a considerable plasticity in the expression of homing receptors has also been observed in some cases. 31,32 Whether this also applies to the expression of CCR6 is not known. In vitro, CCR6 expression can be induced de novo on T-cell receptor (TCR)-stimulated naive T cells by a cocktail of proinflammatory cytokines in combination with transforming growth factor-␤ (TGF-␤). 9 The transcriptional regulation of CCR6 is not well understood; a region with promoter activity has been identified in the mouse CCR6 gene, 33 and overexpression of the transcription factor ROR␥t, the master regulator of Th17 cells, leads to CCR6 expression on human and murine T cells. 10,34 However, whether stable CCR6 expr...

Vaccine-Induced Th17 Cells Are Maintained Long-Term Postvaccination as a Distinct and Phenotypically Stable Memory Subset

“…In agreement with this, we found the induced Th17 cells to be stable and to maintain their dichotomy relative to Th1, thus implying that during the inflammatory quiescent 69-week period from final immunization, the Th17 memory cells did not adopt Th1 phenotypic characteristics. At all times we found the Th17 cells to express significantly higher levels of the mucosal chemokine receptor CCR6 (CD196) than the Th1 T cell lineage, which further reinforces that the vaccine-induced Th17 memory subset is phenotypically stable (2,48).…”

CKR-L3, a deletion version CCR6-isoform shows coreceptor-activity for limited human and simian immunodeficiency viruses

“…Expressions of mRNA of both CKR-L3 and CCR6 were detected by RT-PCR in PBMC, T cell lines, ATL1K and C8166 as well as in hepatic cell lines, such as huH1 and HepG2 (Figure 1b). Similar to our findings, previous reports have showed the expression of CKR-L3 in spleen, lymph nodes and PBMC [15], whereas CCR6 was selectively expressed on Th17 cells and regulatory T cells, memory T cells, B cells and dendritic cells [27,28]. The 15-nucleotide size-difference between the amplified ORFs of CKR-L3 and CCR6 could not be distinguished fairly when they were run through 1.5% agarose gel electrophoresis (Figure 1c).…”

HIV persists in CCR6+CD4+ T cells from colon and blood during antiretroviral therapy

“…Previous studies documented a transient down regulation of CCR6 expression upon TCR triggering [71], raising the possibility that in HIV-infected subjects with chronic systemic immune activation, the CCR6 − fraction may be contaminated by formerly CCR6 + T-cells. To test this possibility, highly pure total memory CCR6 + /CCR6 − T-cells sorted by flow cytometry ( Suppl.…”