Evidence to Support the Role of HLA-G5 in Allograft Acceptance through Induction of Immunosuppressive/ Regulatory T Cells

Abstract

The soluble HLA-G5 isoform encoded by intron-4 retaining spliced transcript has been previously detected in vivo in sera and grafts from transplanted patients who had significantly better graft acceptance. These findings led us to investigate the role of HLA-G5 in tolerance induction in vitro and its biological relevance in allograft acceptance in vivo. We demonstrated that engagement of Ig-like transcript-2 and Ig-like transcript-4 receptors by HLA-G5 is involved in inhibition of T cell alloproliferative responses. Naive T cells sensitized in vitro with HLA-G5, for as little as 18 h, 1) lost their ability to respond to subsequent allogeneic stimulus, and 2) acquired regulatory properties because they inhibited the reactivity of other T cells. These HLA-G5-induced T cells act in an Ag-nonspecific fashion and through soluble factors. Biological relevance was provided by ex vivo analyzes of samples from liver-kidney cotransplanted patients who had high HLA-G5 serum levels and no graft rejection. We showed that addition of HLA-G5-containing sera from these patients inhibited T cell alloresponses and that serum HLA-G5 was responsible for this inhibition. Notably, PBMC from transplanted patients exposed to high levels of circulating HLA-G5 did not respond to allostimulation and inhibited alloreactivity of other T cells. These results demonstrate that HLA-G5-mediated tolerance involves the induction of immunosuppressive T cells. These findings provide evidence supporting the tolerogenic properties of HLA-G and emphasize its potential application as a relevant therapeutic candidate capable of limiting allograft rejection.

HLA-G turns off erythropoietin receptor signaling through JAK2 and JAK2 V617F dephosphorylation: clinical relevance in polycythemia vera

“…Since protein aggregation was previously described as a critical factor for the biological activity of HLA-G5 on immune cells, 11 here we used this protein once aggregated onto microbeads (that is, HLA-G5-beads). We showed that UT7/EPO cell proliferation was significantly reduced by increasing concentrations of HLA-G5-beads (unpaired t-test, Po0.04 for 10 000 HLA-G5-beads per cell; Po0.01 for 20 000 and 30 000 HLA-G5-beads per cell; Po0.003 for 40 000 HLA-G5-beads per cell; n ¼ 3) (Figure 1a).…”

“…11 Briefly, microbeads (Ademtech, Pessac, France) were incubated first with the 5A6G7 antibody to HLA-G5 (Exbio, Prague, Czech Republic) 2 and then with either rHLA-G5-containing medium or HLA-G5-containing plasma samples.…”

Papel de las células dendríticas tolerogénicas ILT3+/ILT4+ en la respuesta inmunitaria a trasplante de órganos y tejidos

“…Mientras el ligando de ILT3 en las células T aún se desconoce, hay evidencia de que ILT4 ejerce sus efectos inmunomoduladores mediante la unión a diferentes moléculas clásicas y no clásicas CMH de clase I, tales como HLA-A, HLA-B y HLA-G1 (69,70 (71,72). Estas fosfatasas citoplásmicas pueden desfosforilar los receptores inmunitarios activados que contienen dominios ITAM, conduciendo a su inactivación, lo cual resulta en una disminución en la capacidad de estímulo por parte de la célula presentadora de antígeno a la célula T, induciendo finalmente una inhibición en la respuesta de esta última (73,74).…”

Soluble HLA-G: Are they clinically relevant?

“…Thus, sHLA-G5 inhibits T cell proliferation induced by allogeneic dendritic cells without affecting their differentiation and maturation [25]. Furthermore, naïve T cells incubated with sHLA-G5 for 18 hours become anergic to subsequent antigenic stimulation and acquire regulatory properties, as demonstrated by their ability to inhibit proliferation of other T cells in an antigen non-specific fashion [26].…”