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PMID: 23677517 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

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

European journal of immunology ·Vol. 43 ·No. 8 ·2013-08-00 ·Pages 2043-54

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

Abstract

Treg cells are critical for the prevention of autoimmune diseases and are thus prime candidates for cell-based clinical therapy. However, human Treg cells are "plastic", and are able to produce IL-17 under inflammatory conditions. Here, we identify and characterize the human Treg subpopulation that can be induced to produce IL-17 and identify its mechanisms. We confirm that a subpopulation of human Treg cells produces IL-17 in vitro when activated in the presence of IL-1β, but not IL-6. "IL-17 potential" is restricted to population III (CD4(+) CD25(hi) CD127(lo) CD45RA(-) ) Treg cells expressing the natural killer cell marker CD161. We show that these cells are functionally as suppressive and have similar phenotypic/molecular characteristics to other subpopulations of Treg cells and retain their suppressive function following IL-17 induction. 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.

Keywords
Conversion Human Regulatory T (Treg) cells STAT3 Th17
MeSH Terms
Adult Aged CD4 Antigens/biosynthesis Cells, Cultured Female Forkhead Transcription Factors/biosynthesis Humans Interleukin-17/biosynthesis Interleukin-1beta/metabolism Interleukin-2 Receptor alpha Subunit/biosynthesis Interleukin-6/metabolism Interleukin-7 Receptor alpha Subunit/biosynthesis Leukocyte Common Antigens/biosynthesis Lymphocyte Activation Male Middle Aged NK Cell Lectin-Like Receptor Subfamily B/immunology,metabolism STAT3 Transcription Factor/genetics,metabolism T-Lymphocytes, Regulatory/immunology,metabolism
Chemicals
CD4 Antigens FOXP3 protein, human Forkhead Transcription Factors Interleukin-17 Interleukin-1beta Interleukin-2 Receptor alpha Subunit Interleukin-6 Interleukin-7 Receptor alpha Subunit NK Cell Lectin-Like Receptor Subfamily B STAT3 Transcription Factor STAT3 protein, human Leukocyte Common Antigens
Authors & Affiliations
21 authors, click to expand affiliations / ORCID
Afzali Behdad
Medical Research Council Centre for Transplantation, King's College London, King's Health Partners, Guy's Hospital, London, UK. susan.john@kcl.ac.uk
Mitchell Peter J
Edozie Francis C
Povoleri Giovanni A M
Dowson Sophie E
Demandt Laura
Walter Gina
Canavan James B
Scotta Cristiano
Menon Bina
Chana Prabhjoat S
Khamri Wafa
Kordasti Shahram Y
Heck Susanne
Grimbacher Bodo
Tree Timothy
Cope Andrew P
Taams Leonie S
Lechler Robert I
John Susan
Lombardi Giovanna
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Article Info
Journal
European journal of immunology
Abbr.
Eur J Immunol
ISSN
1521-4141
DOI
10.1002/eji.201243296
Email
susan.john@kcl.ac.uk
Published
2013-08-00
Epub
2013-00-03
Pages
2043-54
Language
English
Region
Germany
NLM ID
1273201
PMCID
PMC3815561
Subset
IM
Grants
Arthritis Research UK · 19307 · United Kingdom
British Heart Foundation · RG/08/005/25303 · United Kingdom
Medical Research Council · MR/J006742/1 · United Kingdom
Versus Arthritis · 19307 · United Kingdom
Medical Research Council · G0500429 · United Kingdom
Wellcome Trust · 097261 · United Kingdom
Department of Health · DRF-2009-02-22 · United Kingdom
Medical Research Council · G0400197 · United Kingdom
Medical Research Council · MR/K025538/1 · United Kingdom
External Links
PubMed source DOI: 10.1002/eji.201243296 PMC Full Text View journal details
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