Human CD4+ HLA-G+ regulatory T cells are potent suppressors of graft-versus-host disease in vivo.

Autor: Pankratz S; Department of Neurology and., Bittner S; Department of Neurology and., Herrmann AM; Department of Neurology and., Schuhmann MK; Department of Neurology, University of Würzburg, Würzburg, Germany., Ruck T; Department of Neurology and., Meuth SG; Department of Neurology and Institute of Physiology I, Department of Neuropathophysiology, University of Münster, Münster, Germany; and., Wiendl H; Department of Neurology and heinz.wiendl@ukmuenster.de.
Jazyk: angličtina
Zdroj: FASEB journal : official publication of the Federation of American Societies for Experimental Biology [FASEB J] 2014 Aug; Vol. 28 (8), pp. 3435-45. Date of Electronic Publication: 2014 Apr 17.
DOI: 10.1096/fj.14-251074
Abstrakt: 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.
(© FASEB.)
Databáze: MEDLINE
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