Helios+ and Helios- Cells Coexist within the Natural FOXP3+ T Regulatory Cell Subset in Humans

被引:170
作者
Himmel, Megan E. [1 ]
MacDonald, Katherine G. [1 ]
Garcia, Rosa V. [1 ]
Steiner, Theodore S. [2 ]
Levings, Megan K. [1 ]
机构
[1] Univ British Columbia, Child & Family Res Inst, Dept Surg, Vancouver, BC V5Z 4H4, Canada
[2] Univ British Columbia, Dept Med, Div Infect Dis, Vancouver, BC V6H 3Z6, Canada
关键词
TRANSCRIPTION FACTOR; IN-VITRO; EXPRESSION; DISTINCT; NAIVE; DIFFERENTIATION; PROLIFERATION; ACTIVATION; MECHANISMS; SIGNATURE;
D O I
10.4049/jimmunol.1201379
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
FOXP3-expressing T regulatory cells (Tregs) can be divided into two distinct subsets: naturally occurring Tregs (nTregs) that develop in the thymus, and induced Tregs (iTregs) that differentiate in peripheral tissues upon exposure to Ag in a tolerogenic environment. Recently it has been proposed that expression of Helios, an Ikaros family transcription factor, may specifically identify nTregs, allowing specific tracking of Tregs from different origins in health and disease. Surprisingly, we found that Helios(-) cells can be readily identified within naive (CD45RA(+)CD31(+)CCR7(+)CD62L(+)) FOXP3(+) Tregs, a finding inconsistent with the notion that lack of Helios expression identifies Ag-experienced iTregs that should express memory markers. To investigate the phenotype and function of naive Helios(+) and Helios(-) Tregs within the nTreg population, we isolated single-cell clones from each subset. We found that both Helios(+) and Helios(-) nTreg clones have a similar suppressive capacity, as well as expression of FOXP3 and cell surface proteins, including CD39 and CTLA-4. Helios 2 nTregs, however, produced significantly more CCL3 and IFN-gamma compared with Helios(+) nTregs. Despite increased cytokine/chemokine production, Helios 2 FOXP3(+) nTreg clones were demethylated at the FOXP3 Treg-specific demethylated region, indicative of Treg lineage stability. When cultured under Th1-polarizing conditions, Helios(+) and Helios(-) nTreg clones had an equal ability to produce IFN-gamma. Collectively, these data show that a lack of Helios expression does not exclusively identify human iTregs, and, to our knowledge, the data provide the first evidence for the coexistence of Helios(+) and Helios(-) nTregs in human peripheral blood. The Journal of Immunology, 2013, 190: 2001-2008.
引用
收藏
页码:2001 / 2008
页数:8
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