The TNF/TNFR2 signaling pathway is a key regulatory factor in endothelial progenitor cell immunosuppressive effect

Abstract

Background Endothelial progenitor cells (EPCs) are non-differentiated endothelial cells (ECs) present in blood circulation that are involved in neo-vascularization and correction of damaged endothelial sites. Since EPCs from patients with vascular disorders are impaired and inefficient, allogenic sources from adult or cord blood are considered as good alternatives. However, due to the reaction of immune system against allogenic cells which usually lead to their elimination, we focused on the exact role of EPCs on immune cells, particularly, T cells which are the most important cells applied in immune rejection. TNFα is one of the main activators of EPCs that recognizes two distinct receptors. TNFR1 is expressed ubiquitously and its interaction with TNFα leads to differentiation and apoptosis, whereas, TNFR2 is expressed predominantly on ECs, immune cells and neural cells and is involved in cell survival and proliferation. Interestingly, it has been shown that different immunosuppressive cells express TNFR2 and this is directly related to their immunosuppressive efficiency. However, little is known about immunological profile and function of TNFR2 in EPCs. Methods Using different in-vitro combinations, we performed co-cultures of ECs and T cells to investigate the immunological effect of EPCs on T cells. We interrupted in the TNFα/TNFR2 axis either by blocking the receptor using TNFR2 antagonist or blocking the ligand using T cells derived from TNFα KO mice. Results We demonstrated that EPCs are able to suppress T cell proliferation and modulate them towards less pro-inflammatory and active phenotypes. Moreover, we showed that TNFα/TNFR2 immune-checkpoint pathway is critical in EPC immunomodulatory effect. Conclusions Our results reveal for the first time a mechanism that EPCs use to suppress immune cells, therefore, enabling them to form new immunosuppressive vessels. Furthermore, we have shown the importance of TNFα/TNFR2 axis in EPCs as an immune checkpoint pathway. We believe that targeting TNFR2 is especially crucial in cancer immune therapy since it controls two crucial aspects of tumor microenvironment: 1) Immunosuppression and 2) Angiogenesis.

TNFα priming through its interaction with TNFR2 enhances Endothelial Progenitor Cell immunosuppressive effect: a new hope for their widespread clinical application

“…We have recently demonstrated that EPCs bear immunosuppressive effect, secrete anti-in ammatory cytokines and are tolerated for certain days after their administration in xenogeneic ischemia model. 30,31 However, our experience demonstrates that compared to other immunosuppressive cells like Tregs and MSCs, EPCs are signi cantly less suppressive. This could potentially affect the success of cell therapy outcome.…”

“…Compared to APB-EPCs, CB-EPCs are more clonogenic, e cient and immunotolerated. 19,20,30 Nevertheless, the choice of allogenic sources usually raise the concern of immune rejection risking the achievement of the desired bene t.…”

“…We previously demonstrated that ECFCs can suppress T cells and this effect was dependent on the production of TNFα by activated T cells and the expression of TNFR2 by ECFCs ( Figure 3A). 29,30 Here, we aimed to explore if the pre-treatment of ECFCs with TNFα could boost TNFR2 expression and consequently their immunosuppressive effect ( Figure 3B).…”

“…53,54,73,74 Our recent results proved that ECFCs are also sharing the same mechanism. 30 Indeed, in ammatory factors, like IL-1, TNFα and IFNγ, enhance MSC and Treg immunoregulatory functions mostly through promoting the secretion of immunoregulatory factors like PGE2, IDO, HGF, IL-10 and TGFβ. 46,55,[75][76][77][78] Therefore, the main purpose of our study was to up-regulate TNFR2 immune checkpoint molecule on ECFCs via pre-treating them with proper dose of TNFα and prime them towards accentuated immunosuppressive effect.…”

Human Fetal Liver MSCs are More Effective Than Adult Bone Marrow MSCs for Their Immunosuppressive, Immunomodulatory and Foxp3+ T regs Induction Capacity

“…Although FL-MSCs gave rise to more iT regs than BM-MSCs, both were able to induce Foxp3 expression. To better de ne iT regs induced in the presence of FL and BM-MSC, we characterized them and compared their activation/suppressive pro le by FACS using different activation/suppressive markers, such as CTLA4, GITR and ICOS, [83][84][85] . We focused our analysis on commonly accepted CD4 + Foxp3 + iT regs.…”