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CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner.

Afzali B, Mitchell PJ, Edozie FC, Povoleri GA, Dowson SE, Demandt L, Walter G, Canavan JB, Scotta C, Menon B, Chana PS, Khamri W, Kordasti SY, Heck S, Grimbacher B, Tree T, Cope AP, Taams LS, Lechler RI, John S, Lombardi G - Eur. J. Immunol. (2013)

Bottom Line: Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17.Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites.As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK. susan.john@kcl.ac.uk

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Immunophenotyping of freshly isolated population III CD161+ Treg cells. (A) The percentages of Treg cells staining positive for CD39 (left) and HLA-DR (right) in population III CD161− and CD161+ Treg cells is shown. Paired data from five independent experiments are shown. (B–G) Gene expression profiling of freshly isolated population I CD161−, population III CD161−, and population III CD161+ Treg cells for (B) FOXP3, (C) RORC, (D) FOXP3/RORC ratio, (E) CTLA-4, (F) ICOS, and (G) Helios is shown. Individual data from three independent healthy donors are shown.
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fig04: Immunophenotyping of freshly isolated population III CD161+ Treg cells. (A) The percentages of Treg cells staining positive for CD39 (left) and HLA-DR (right) in population III CD161− and CD161+ Treg cells is shown. Paired data from five independent experiments are shown. (B–G) Gene expression profiling of freshly isolated population I CD161−, population III CD161−, and population III CD161+ Treg cells for (B) FOXP3, (C) RORC, (D) FOXP3/RORC ratio, (E) CTLA-4, (F) ICOS, and (G) Helios is shown. Individual data from three independent healthy donors are shown.

Mentions: Population III CD161+ Treg cells were further characterized to determine how similar they are to other Treg-cell subpopulations at baseline. We first examined expression of CD39, an ecto-enzyme involved in Treg-cell function [38], and HLA-DR, a marker of Treg cells with early contact-dependent suppression [39], by flow cytometry, comparing CD161− with CD161+ Treg cells in population III and found no significant differences between the percentages of Treg cells that express these markers on the two subpopulations, although there was a tendency to lower expression of CD39 (Fig. 4A). Likewise, we compared expression of FOXP3, RORC, CTLA-4 (essential for Treg-cell function [40]), ICOS (Inducible T-cell co-stimulator; ICOS+ Treg cells suppress DCs via IL-10 and TGF-β [41]), and Helios (a putative marker of thymically derived Treg cells [42]) by qRT-PCR on populations I CD161−, III CD161−, and III CD161+ Treg cells obtained from freshly sorted healthy donor Treg cells (Fig. 4B–G). As noted above, population III CD161+ Treg cells express less FOXP3 than the other populations (Fig. 4B) and variable basal levels of RORC with a tendency for higher expression in CD161+ cells (Fig. 4C), resulting in a quantitative FOXP3/RORC mRNA ratio in population III CD161+ Treg cells that favors RORC, compared with that of the other two populations (Fig. 4D).


CD161 expression characterizes a subpopulation of human regulatory T cells that produces IL-17 in a STAT3-dependent manner.

Afzali B, Mitchell PJ, Edozie FC, Povoleri GA, Dowson SE, Demandt L, Walter G, Canavan JB, Scotta C, Menon B, Chana PS, Khamri W, Kordasti SY, Heck S, Grimbacher B, Tree T, Cope AP, Taams LS, Lechler RI, John S, Lombardi G - Eur. J. Immunol. (2013)

Immunophenotyping of freshly isolated population III CD161+ Treg cells. (A) The percentages of Treg cells staining positive for CD39 (left) and HLA-DR (right) in population III CD161− and CD161+ Treg cells is shown. Paired data from five independent experiments are shown. (B–G) Gene expression profiling of freshly isolated population I CD161−, population III CD161−, and population III CD161+ Treg cells for (B) FOXP3, (C) RORC, (D) FOXP3/RORC ratio, (E) CTLA-4, (F) ICOS, and (G) Helios is shown. Individual data from three independent healthy donors are shown.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3815561&req=5

fig04: Immunophenotyping of freshly isolated population III CD161+ Treg cells. (A) The percentages of Treg cells staining positive for CD39 (left) and HLA-DR (right) in population III CD161− and CD161+ Treg cells is shown. Paired data from five independent experiments are shown. (B–G) Gene expression profiling of freshly isolated population I CD161−, population III CD161−, and population III CD161+ Treg cells for (B) FOXP3, (C) RORC, (D) FOXP3/RORC ratio, (E) CTLA-4, (F) ICOS, and (G) Helios is shown. Individual data from three independent healthy donors are shown.
Mentions: Population III CD161+ Treg cells were further characterized to determine how similar they are to other Treg-cell subpopulations at baseline. We first examined expression of CD39, an ecto-enzyme involved in Treg-cell function [38], and HLA-DR, a marker of Treg cells with early contact-dependent suppression [39], by flow cytometry, comparing CD161− with CD161+ Treg cells in population III and found no significant differences between the percentages of Treg cells that express these markers on the two subpopulations, although there was a tendency to lower expression of CD39 (Fig. 4A). Likewise, we compared expression of FOXP3, RORC, CTLA-4 (essential for Treg-cell function [40]), ICOS (Inducible T-cell co-stimulator; ICOS+ Treg cells suppress DCs via IL-10 and TGF-β [41]), and Helios (a putative marker of thymically derived Treg cells [42]) by qRT-PCR on populations I CD161−, III CD161−, and III CD161+ Treg cells obtained from freshly sorted healthy donor Treg cells (Fig. 4B–G). As noted above, population III CD161+ Treg cells express less FOXP3 than the other populations (Fig. 4B) and variable basal levels of RORC with a tendency for higher expression in CD161+ cells (Fig. 4C), resulting in a quantitative FOXP3/RORC mRNA ratio in population III CD161+ Treg cells that favors RORC, compared with that of the other two populations (Fig. 4D).

Bottom Line: Importantly, we find that IL-17 production is STAT3 dependent, with Treg cells from patients with STAT3 mutations unable to make IL-17.Finally, we show that CD161(+) population III Treg cells accumulate in inflamed joints of patients with inflammatory arthritis and are the predominant IL-17-producing Treg-cell population at these sites.As IL-17 production from this Treg-cell subpopulation is not accompanied by a loss of regulatory function, in the context of cell therapy, exclusion of these cells from the cell product may not be necessary.

View Article: PubMed Central - PubMed

Affiliation: Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK. susan.john@kcl.ac.uk

Show MeSH
Related in: MedlinePlus