Immunoevasive Pericytes From Human Pluripotent Stem Cells Preferentially Modulate Induction of Allogeneic Regulatory T Cells

Abstract

Isolated microvessel-residing pericytes and pericytes from human pluripotent stem cells (hPSCs) exhibit mesenchymal stem cell-like characteristics and therapeutic properties. Despite growing interest in pericyte-based stem cell therapy, their immunogenicity and immunomodulatory effects on nonactivated T cells are still poorly defined, in particular those of vasculogenic hPSC pericytes. We found that tissue-embedded and unstimulated cultured hPSC-or tissue-derived pericytes constitutively expressed major histocompatibility complex (MHC) class I and the inhibitory programmed cell death-ligand 1/2 (PD-L1/2) molecules but not MHC class II or CD80/CD86 costimulatory molecules. Pretreatment with inflammatory mediators failed to induce an antigen-presenting cell-like phenotype in stimulated pericytes. CD146+ pericytes from hPSCs did not induce activation and proliferation of allogeneic resting T cells independent of interferon (IFN)-g prestimulation, similarly to pericytes from human brain or placenta. Instead, pericytes mediated a significant increase in the frequency of allogeneic CD25 2 T cells maintained a nonimmunogenic phenotype and mediated the development of functional regulatory T cells. Together, these findings reveal a novel feature of pericytemediated immunomodulation distinguished from immunosuppression, shared by native tissue pericytes and hPSC pericytes, and support the notion that pericytes can be applied for allogeneic cell therapy. STEM CELLS

Immune Regulation by Pericytes: Modulating Innate and Adaptive Immunity

“…As previously described, incubation of cultured PC with IFN-γ induced the expression of MHC class II by all types of PC. On the contrary, IFN-γ did not stimulate the expression of CD80 or CD86 and did not significantly affect the proliferation of CFSE-labeled CD4 + T cells in comparison with untreated PC (40). …”

“…PD-L1/2 expression and secretion of TGF-β by hPSC PC directly regulated generation of Tregs favoring allostimulation of Tregs over T cell activation, suggesting that hPSC PC could be applied to allogeneic cell therapy in the clinic, not only without provoking immediate immune responses but also actively modulating suppressive immunity (40). …”

Targeted Disruption of the β2-Microglobulin Gene Minimizes the Immunogenicity of Human Embryonic Stem Cells

“…The absorbance of the samples was measured at a 490‐nm wavelength to determine the lactate dehydrogenase activity. To examine in vivo CD8 + T cell‐ and NK cell‐mediated response to transplanted hESCs, 4 × 10 6 hESCs or B2M −/− hESCs were mixed with 200 ml of growth factor‐reduced Matrigel and injected subcutaneously into 10‐week‐old immunocompetent mice [41]. The implants were harvested after 48 hours for immunofluorescence staining of CD8 + T cells or KLRA1 + NK cells.…”

Concise Review: The Regenerative Journey of Pericytes Toward Clinical Translation

“…The ability of pericytes to regulate the immune response is an important property for a regenerative cell type as it opens up the possibility of allogenic cell therapy. The major reason for transplant rejection is the response of the adaptive immune system to alloantigens through activation of T cells . Activation of T cells is regulated via three signals: antigen presentation via cell surface major histocompatibility complex (MHC) class I or II stimulatory molecules, costimulation with costimulatory molecules, and secretion of cytokines .…”