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Human CD4 + HLA‐G + regulatory T cells are potent suppressors of graft‐versus‐host disease in vivo
- Source :
- The FASEB Journal. 28:3435-3445
- Publication Year :
- 2014
- Publisher :
- Wiley, 2014.
-
Abstract
- CD4(+) T cells expressing the immunotolerizing molecule HLA-G have been described as a unique human thymus-derived regulatory T (tTreg) cell subset involved in immunoregulation and parenchymal homeostasis during infectious and autoimmune inflammation. We compared properties and molecular characteristics of human CD4(+)HLA-G(+) with those of CD4(+)CD25(+)FoxP3-expressing tTreg cells using in vitro studies of T-cell receptor (TCR) signaling, single-cell electrophysiology, and functional in vivo studies. Both tTreg populations are characterized by alterations in proximal-signaling pathways on TCR stimulation and a hyperpolarization of the plasma membrane when compared to conventional CD4(+) T cells. However, both clearly differ in phenotype and pattern of secreted cytokines, which results in distinct mechanisms of suppression: While CD4(+)HLA-G(+) cells secrete high levels of inhibitory molecules (IL-10, soluble HLA-G, IL-35), CD4(+)CD25(+)FoxP3(+) cells express these molecules at significantly lower levels and seem to exert their function mainly in a contact-dependent manner via cyclic adenosine-monophosphate. Finally we demonstrate that human CD4(+)HLA-G(+) tTreg cells significantly ameliorated graft-versus-host disease in a humanized mouse model as a first proof of their in vivo relevance. Our data further characterize and establish CD4(+)HLA-G(+) cells as a potent human tTreg population that can modulate polyclonal adaptive immune responses in vivo and thus being a promising candidate for potential clinical applications in the future.
- Subjects :
- CD4-Positive T-Lymphocytes
Graft vs Host Disease
Human leukocyte antigen
Biology
Lymphocyte Activation
T-Lymphocytes, Regulatory
Biochemistry
Membrane Potentials
Immune tolerance
Mice
Mice, Inbred NOD
T-Lymphocyte Subsets
HLA-G
Genetics
Animals
Humans
Calcium Signaling
IL-2 receptor
Molecular Biology
HLA-G Antigens
Immunosuppression Therapy
T-cell receptor
Interleukin-2 Receptor alpha Subunit
FOXP3
Forkhead Transcription Factors
Hyperpolarization (biology)
Adoptive Transfer
In vitro
Specific Pathogen-Free Organisms
Cell biology
Immunology
Leukocytes, Mononuclear
Cytokines
Heterografts
Biotechnology
Subjects
Details
- ISSN :
- 15306860 and 08926638
- Volume :
- 28
- Database :
- OpenAIRE
- Journal :
- The FASEB Journal
- Accession number :
- edsair.doi.dedup.....20bec1c3d6f136cc0c2663d0ccdab224