Human Adipose Tissue-Derived Mesenchymal Stromal Cells Inhibit CD4+ T Cell Proliferation and Induce Regulatory T Cells as Well as CD127 Expression on CD4+CD25+ T Cells

Abstract

Mesenchymal stromal cells (MSC) exert their immunomodulatory potential on several cell types of the immune system, affecting and influencing the immune response. MSC efficiently inhibit T cell proliferation, reduce the secretion of pro-inflammatory cytokines, limit the differentiation of pro-inflammatory Th subtypes and promote the induction of regulatory T cells (Treg). In this study, we analyzed the immunomodulatory potential of human adipose tissue-derived MSC (ASC), on CD4+ T cells, addressing potential cell-contact dependency in relation to T cell receptor stimulation of whole human peripheral blood mononuclear cells (PBMC). ASC were cultured with not stimulated or anti-CD3/CD28-stimulated PBMC in direct and transwell cocultures; PBMC alone were used as controls. After 7 days, cocultures were harvested and we analyzed: (1) the inhibitory potential of ASC on CD4+ cell proliferation and (2) phenotypic changes in CD4+ cells in respect of Treg marker (CD25, CD127 and FoxP3) expression. We confirmed the inhibitory potential of ASC on CD4+ cell proliferation, which occurs upon PBMC stimulation and is mediated by indoleamine 2,3-dioxygenase. Importantly, ASC reduce both pro- and anti-inflammatory cytokine secretion, without indications on specific Th differentiation. We found that stimulation induces CD25 expression on CD4+ cells and that, despite inhibiting overall CD4+ cell proliferation, ASC can specifically induce the proliferation of CD4+CD25+ cells. We observed that ASC induce Treg (CD4+CD25+CD127−FoxP3+) only in not stimulated cocultures and that ASC increase the ratio of CD4+CD25+CD127+FoxP3− cells at the expense of CD4+CD25+CD127−FoxP3− cells. Our study provides new insights on the interplay between ASC and CD4+ T cells, proposing that ASC-dependent induction of Treg depends on PBMC activation which affects the balance between the different subpopulations of CD4+CD25+ cells expressing CD127 and/or FoxP3.

Mesenchymal Stem Cell Induced Foxp3(+) Tregs Suppress Effector T Cells and Protect against Retinal Ischemic Injury

“…Importantly, we also demonstrated that the increased recruitment of Foxp3+Tregs in the retina correlated with dampened retinal inflammation and improved b-wave amplitudes in the I/R injury model. Our findings are in keeping with published data by others that have demonstrated Tregs act as part of the adaptive immune system, and thereby (A) serve as important regulators of inflammation and play a critical role in immune homeostasis [ 14 ]; (B) are inversely correlated with retinal ischemia [ 34 ]; and (C) are well known for immunomodulation, with recent evidence suggesting that MSCs can enhance Foxp3+Treg differentiation and stability from activated T cells in part through mitochondrial transfer [ 12 , 13 , 35 ].…”

“…The suppression of immune cell activation is one of the manifestations of MSC-mediated immunomodulation [ 12 , 26 ]. To assess whether mitochondrial transfer from stem cells to primary mouse splenocytes impacts T-cell differentiation, activated splenocytes were cocultured with iMSCs or ASCs and subsequently assessed for the expression of T regulatory cells ( Figure 5 A and Supplemental Figure S4 ).…”

“…Recent evidence suggests that MSCs can modulate Tregs [ 12 ], particularly Tregs expressing the Foxp3 transcription factor, part of the adaptive immune system and principal regulators of inflammation and immune homeostasis [ 14 ]. Although Tregs primarily originate in the thymus (tTregs), during tissue damage, the CD4+ (T H ) cells at the site of injury can also be reprogrammed and acquire the Treg phenotype, also known as peripheral Tregs (pTregs) and regulate immunotolerance [ 19 ].…”

“…MSCs are well known for being involved in immunomodulation, in part by donating mitochondria to damaged tissue or cells [ 9 , 10 , 11 ]. Recent evidence also suggests that MSCs can modulate T regulatory cells (Tregs) [ 12 , 13 ], in particular, Tregs expressing the Forkhead box P3 (Foxp3) transcription factor, which is part of the adaptive immune system and are principal regulators of inflammation and immune homeostasis [ 14 ]. The Tregs can migrate to the diseased tissue and dampen inflammation by increasing the milieu of anti-inflammatory cytokines and activating macrophages to clear the debris and restore the damaged tissue [ 15 , 16 , 17 ].…”

Emodin inhibits the progression of acute pancreatitis via regulation of lncRNA TUG1 and exosomal lncRNA TUG1

“…PBMCs were collected as described in a previous study (32). In brief, CD4 + T cells were isolated from PBMCs, and then CD4 + T cells were treated with 10 ng/ml IL-2 and 2 µg/ml anti-CD3/CD28 for 72 h in order to induce the activation of Treg cells (33).…”