Regulatory T cell induction by mesenchymal stem cells depends on the expression of TNFR2 by T cells
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(2020) 11:534
SHORT REPORT
Open Access
Regulatory T cell induction by mesenchymal stem cells depends on the expression of TNFR2 by T cells Sina Naserian1,2,3*† , Sara Shamdani1,2,3†, Nassim Arouche1,2 and Georges Uzan1,2
Abstract Mesenchymal stem/stromal cells can modulate the effector immune cells especially T lymphocytes. Due to this important feature, they can regulate the development of a variety of disorders including inflammatory and autoimmune disorders, cancers, and transplantation outcomes. One of the most important MSC immunoregulatory functions is their capacity to convert conventional T cells into regulatory T cells. Several mechanisms, mostly related to MSCs but not T cells, have been shown essential for this aspect. The inflammatory microenvironment majorly caused by pro-inflammatory cytokines has been demonstrated to govern the direction of the immune response. In this respect, we have recently revealed that the TNFα-TNFR2 signaling controls several aspects of MSC immunomodulatory properties including their ability to suppress T cells and their conversion towards Foxp3expressing Tregs. Here in this work, we have looked from another angle by investigating the impact of TNFR2 expression by T cells on their ability to be converted to suppressive Tregs by MSCs. We showed that unlike WT-T cells, their TNFR2 KO counterparts are remarkably less able to convert into Foxp3+ and Foxp3− Tregs. Furthermore, TNFR2 blockade diminished the anti-inflammatory cytokine secretion by iTregs and consequently resulted in less T cell immunosuppression. This work is the first evidence of the crucial association of TNFR2 expression by T cells with their iTreg conversion capacity by MSCs. It strengthens once more the potential of anti-TNFR2 administration for a strong and effective interference with the immunosuppression exerted by TNFR2-expressing cells. Keywords: Mesenchymal stem cells, Regulatory T cells, TNF-TNFR2 signaling pathway, Immune checkpoint, Immunosuppression, Immunoregulation, Immune therapy
Background Mesenchymal stem/stromal cells (MSCs) are multipotent stem cells with unique biological potentials. Among them, their regenerative and immunoregulatory functions are the most important, making them the ideal choices for cell therapy applications. MSCs are able to modulate immune cells especially T lymphocytes. They can suppress conventional T cells (Tconvs) and convert * Correspondence: [email protected]; [email protected] † Sina Naserian and Sara Shamdani contributed equally to this work. 1 INSERM UMR-S-MD 1197, Hôpital Paul Brousse, Villejuif, France 2 Paris-Saclay University, Villejuif, France Full list of author information is available at the end of the article
them to regulatory T cells (Tregs) [1]. Indeed, we and others have reported several mechanisms behind their capacity to induce Tregs. The modulation of ubiquitination factors [2], Treg-specific demethylated region (TSDR) demethylation [2], microRNAs such as miR126a [3], and runt-related transcription factor (RUNX) complex are som
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