Human CD4+HLA‐G+ regulatory T cells are potent suppressors of graft‐versus‐host disease in vivo. Issue 8 (17th April 2014)

• Record Type: Journal Article
• Authors: Pankratz, Susann; Bittner, Stefan; Herrmann, Alexander M.; Schuhmann, Michael K.; Ruck, Tobias; Meuth, Sven G.; Wiendl, Heinz
• Is Part Of: FASEB journal. Volume 28:Issue 8(2014)
• Page Start: 3435
• Page End: 3445
• Publication Date: 2014-04-17
• Subjects: human leukocyte antigen G -- immune tolerance -- humanized mouse model -- membrane potential of tTreg cells; Biology -- Periodicals; Biology, Experimental -- Periodicals; 570
• DOI: 10.1096/fj.14-251074
• Languages: English
• ISSNs: 0892-6638

Abstract

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.—Pankratz, S., Bittner, S., Herrmann, A. M., Schuhmann, M. K., Ruck, T., Meuth, S. G., Wiendl, H. Human CD4 + HLA‐G + regulatory T cells are potent suppressors of graft‐versus‐host disease in vivo . FASEB J. 28, 3435‐3445 (2014). www.fasebj.org