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

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 perk cytes. CD146(+) pericytes from hPSCs did not induce activation and proliferation of allogeneic resting T cells independent of interferon (IFN)-gamma prestimulation, similarly to pericytes from human brain or placenta. Instead, pericytes mediated a significant increase in the frequency of allogeneic CD25(high)FoxP3(+) regulatory T cells when cocultured with nonactivated peripheral blood T cells. Furthermore, when peripheral blood CD25(high) regulatory T cells (Tregs) were depleted from isolated CD3(+) T cells, pericytes preferentially induced de novo formation of CD4(+)CD25(high)FoxP3(+)CD127(-), suppressive regulatory T cells. Constitutive expression of PD-L1/2 and secretion of transforming growth factor-beta by hPSC pericytes directly regulated generation of pericyte-induced Tregs. Pericytes cotransplanted into immunodeficient mice with allogeneic CD25(-) T cells maintained a nonimmunogenic phenotype and mediated the development of functional regulatory T cells. Together, these findings reveal a novel feature of pericyte-mediated 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.