Activated Mesenchymal Stromal Cells Process and Present Antigens Regulating Adaptive Immunity

Abstract

Mesenchymal stromal cells (MSCs) are inherently immunomodulatory through production of inhibiting soluble factors and expression of immunosuppressive cell surface markers. We tested whether activated MSCs qualify for the induction of antigen-specific immune regulation. Bone marrow derived human MSCs were activated by interferon-γ and analyzed for antigen uptake and processing and immune regulatory features including phenotype, immunosuppressive capacity, and metabolic activity. To assess whether activated MSC can modulate adaptive immunity, MSCs were pulsed with islet auto-antigen (GAD65) peptide to stimulate GAD65-specific T-cells. We confirm that inflammatory activation of MSCs increased HLA class II, PD-L1, and intracellular IDO expression, whereas co-stimulatory molecules including CD86 remained absent. MSCs remained locked in their metabolic phenotype, as activation did not alter glycolytic function or mitochondrial respiration. MSCs were able to uptake and process protein. Activated HLA-DR3-expressing MSCs pulsed with GAD65 peptide inhibited proliferation of HLA-DR3-restricted GAD65-specific T-cells, while this HLA class II expression did not induce cellular alloreactivity. Conditioning of antigen-specific T-cells by activated and antigen-pulsed MSCs prevented T-cells to proliferate upon subsequent activation by dendritic cells, even after removal of the MSCs. In sum, activation of MSCs with inflammatory stimuli turns these cells into suppressive cells capable of mediating adaptive regulation of proinflammatory pathogenic T-cells.

Mesenchymal Stromal Cells from Fetal and Maternal Placenta Possess Key Similarities and Differences: Potential Implications for Their Applications in Regenerative Medicine

“…Both fetal and maternal cells express HLA-ABC and the co-stimulatory molecule CD95, which could confer the low antigen-presenting properties observed. Moreover, it was reported that IFN-γ stimulation augments the expression of HLA-ABC, HLA-DR, and CD40 in hAMSC [84], and the expression of these immunogenic markers could be responsible for their stimulatory activities, as observed for MSC from other sources [85,86].…”

Mesenchymal Stem Cells Beyond Regenerative Medicine

“…Other immunomodulatory observations upon IFN-γ licensing of antigen-pulsed MSCs are also recorded (van Megen et al, 2019). For example, IFN-γ treatment is associated with the upregulation of B7-H1 (PD-L1) (Krampera et al, 2006).…”

“…Importantly, the study also shows that despite their IFN-γ-induced antigen presentation, MSCs inhibit autoreactive T-cells, an observation associated with PD-L1 upregulation and IDO secretion (Figure 1). The inhibitory effect even lasted beyond the removal of MSCs and the introduction of activation signals (antigen-pulsed DCs) (van Megen et al, 2019). However, in another report, IFNγ-induced upregulation of PD-L1 on antigen-presenting MSCs is believed to be tied to T-cell induction rather than inhibition (Stagg et al, 2006).…”

“…The generated anti-E7 antibodies were, therefore, able to recognize tumors and eventually suppress their growth (Wei et al, 2011). Third and most importantly, MSCs can act as APCs capable of processing and presenting exogenous antigens to activate immune cells; this asset surfaces in response to IFN-γ treatment which induces MSC expression of MHCI/II molecules (Majumdar et al, 2003;Stagg et al, 2006;François et al, 2009;Tomchuck et al, 2012;van Megen et al, 2019). This property was exploited in cancer vaccination studies, which are hitherto limited.…”

Mesenchymal Stromal Cell Immunology for Efficient and Safe Treatment of Osteoarthritis

“…However, some studies reported that MSCs may express these molecules and lose their hypoimmunogenic/immune privileged state. For example, treatment with interferon gamma (IFNγ), which represents an inflammatory environment, induces the expression of MHC class II molecules and increases the expression of MHC class I molecules (Romieu-Mourez et al, 2007;Van Megen et al, 2019).…”