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

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.

Human T cells in silico: Modelling their electrophysiological behaviour in health and disease

“…10 A) and resemble those recorded from living cells ( Fig. 7A; (Pankratz et al, 2014)). Switching to the pathophysiological pH value of 6.0 decreased the total transmembrane current in the resting (122 pA; Table 1, Fig.…”

Targeting Voltage-Dependent Calcium Channels with Pregabalin Exerts a Direct Neuroprotective Effect in an Animal Model of Multiple Sclerosis

“…Fluorescence was measured with a TECAN infinite M200Pro fluorimeter (Tecan Group Ltd., Männerdorf, Switzerland). Excitation was alternated between 340 and 380 nm, and emission was measured at 509 nm every 3 seconds [36].…”

Evaluation of membrane-bound and soluble forms of human leucocyte antigen-G in systemic sclerosis

“…Secondly, we found that the percentage of CD4 1 cells and CD8 1 cells expressing HLA-G molecules was significantly higher in SSc patients than in controls. These CD4 1 HLA-G 1 and CD8 1 HLA-G 1 cells, that are different from the naturally occurring CD25 1 forkhead box protein 3 (FoxP3 1 ) T regs , may be involved in the modulation of immune responses in systemic sclerosis, as it has been reported that these HLA-G-expressing lymphocytes exert potent suppressive function and are present in inflamed tissues of patients affected by immune mediated disorders [50,63,64]. Interestingly, HLA-G molecules were detected in epidermal and dermal cells of skin biopsies from approximately 50% of patients with SSc, and HLA-G expression was associated with a lower frequency of cutaneous ulcers, telangiectasias and polyarthralgias [53].…”