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Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6298-6307. doi: 10.1073/pnas.1812471116. Epub 2019 Mar 7.

Microenvironment tailors nTreg structure and function.

Author information

1
Laboratory of Oncodermatology, Immunology, and Cutaneous Stem Cells, INSERM U976, 75010 Paris, France.
2
Institut de Recherche Saint-Louis, Paris Diderot University, Sorbonne Paris Cité, 75010 Paris, France.
3
Institut de Recherche Saint-Louis, UMR CNRS 7212, Hôpital Saint-Louis, 75010 Paris, France.
4
Institut Jules Bordet, Université Libre de Bruxelles, 1000 Brussels, Belgium.
5
Laboratory for Genomics, Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain, 75010 Paris, France.
6
Department of Dermatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, 75010 Paris, France.
7
Université Catholique de Louvain, Centre Hospitalo-Universitaire - Université Catholique de Louvain (CHU UCL) Namur, 5530 Yvoir, Belgium.
8
Laboratory for Bioinformatics, Fondation Jean Dausset Centre d'Etude du Polymorphisme Humain, 75010 Paris, France.
9
Technical Support, eBioscience, an Affymetrix Company, 91941 Courtaboeuf, France.
10
Cell Therapy Unit and Clinical Investigation Center in Biotherapies (CBT501), AP-HP, Hôpital Saint-Louis, 75010 Paris, France.
11
Service de Pharmacologie et d'Immunoanalyse, Commissariat à L'énergie Atomique, INRA, Université Paris-Saclay, 91190 Gif-Sur-Yvette, France.
12
Research Department, Neovacs, 75014 Paris, France.
13
Pathophysiology, Targets and Therapy of Rheumatoid Arthritis, INSERM UMR1125, Université Paris 13, Sorbonne Paris Cité, 93000 Bobigny, France.
14
Department of Rheumatology, AP-HP, Hôpital Avicenne, 93000 Bobigny, France.
15
Molecular Biology Department, Université of Liège, 4000 Liège, Belgium.
16
Institute of Human Virology, University of Maryland School of Medicine, Baltimore, MD 21201 rgallo@ihv.umaryland.edu dzagury@free.fr.
17
Research Department, Neovacs, 75014 Paris, France; rgallo@ihv.umaryland.edu dzagury@free.fr.

Abstract

Natural regulatory T cells (nTregs) ensure the control of self-tolerance and are currently used in clinical trials to alleviate autoimmune diseases and graft-versus-host disease after hematopoietic stem cell transfer. Based on CD39/CD26 markers, blood nTreg analysis revealed the presence of five different cell subsets, each representing a distinct stage of maturation. Ex vivo added microenvironmental factors, including IL-2, TGFβ, and PGE2, direct the conversion from naive precursor to immature memory and finally from immature to mature memory cells, the latest being a no-return stage. Phenotypic and genetic characteristics of the subsets illustrate the structural parental maturation between subsets, which further correlates with the expression of regulatory factors. Regarding nTreg functional plasticity, both maturation stage and microenvironmental cytokines condition nTreg activities, which include blockade of autoreactive immune cells by cell-cell contact, Th17 and IL-10 Tr1-like activities, or activation of TCR-stimulating dendritic cell tolerization. Importantly, blood nTreg CD39/CD26 profile remained constant over a 2-y period in healthy persons but varied from person to person. Preliminary data on patients with autoimmune diseases or acute myelogenous leukemia illustrate the potential use of the nTreg CD39/CD26 profile as a blood biomarker to monitor chronic inflammatory diseases. Finally, we confirmed that naive conventional CD4 T cells, TCR-stimulated under a tolerogenic conditioned medium, could be ex vivo reprogrammed to FOXP3 lineage Tregs, and further found that these cells were exclusively committed to suppressive function under all microenvironmental contexts.

KEYWORDS:

CD39 regulatory receptor; FOXP3 regulatory transcript; adenosine deaminase-binding CD26; microenvironmental cytokines; nTregs

PMID:
30846549
PMCID:
PMC6442590
DOI:
10.1073/pnas.1812471116
[Indexed for MEDLINE]
Free PMC Article

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