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Human placental pericytes poorly stimulate and actively regulate allogeneic CD4 T cell responses.

ABSTRACT: Cell-mediated immune responses in peripheral tissues begin with T cell infiltration through endothelial cell (EC) microvessels and accumulation in the perivascular space occupied by pericytes (PC). Here, we investigate how human T cells interact with PC.We compared human placental PC with autologous umbilical vein EC. Cultured PC express lower levels of major histocompatibility complex (MHC) and positive costimulatory molecules but higher levels of negative costimulatory molecules than do EC. Unlike EC, interferon-?-treated MHC class II-positive PC (PC(+)) cannot stimulate resting allogeneic CD4 T cell proliferation or cytokine production. Instead, coculture of resting CD4 T cells with PC(+) induces CD25 expression and renders T cells unresponsive to restimulation by EC(+) from the same donor. PC cultured across a semi-permeable membrane decrease alloreactive CD4 T cell proliferation to EC(+), an effect enhanced by pretreatment of PC with interferon-? and partially reversed by interleukin-10 and transforming growth factor-? neutralization, but do not induce anergy.Human placental PC are poorly immunogenic and negatively regulate CD4 T cell responses through contact-dependent and contact-independent mechanisms.

SUBMITTER: Maier CL

PROVIDER: S-EPMC3380367 | biostudies-literature | 2011 Jan

REPOSITORIES: biostudies-literature

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Human placental pericytes poorly stimulate and actively regulate allogeneic CD4 T cell responses.

Maier Cheryl L CL Pober Jordan S JS

Arteriosclerosis, thrombosis, and vascular biology 20101104 1

<h4>Objective</h4>Cell-mediated immune responses in peripheral tissues begin with T cell infiltration through endothelial cell (EC) microvessels and accumulation in the perivascular space occupied by pericytes (PC). Here, we investigate how human T cells interact with PC.<h4>Methods and results</h4>We compared human placental PC with autologous umbilical vein EC. Cultured PC express lower levels of major histocompatibility complex (MHC) and positive costimulatory molecules but higher levels of n ...[more]

PMID: 21051666

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Project description: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)-γ prestimulation, similarly to pericytes from human brain or placenta. Instead, pericytes mediated a significant increase in the frequency of allogeneic CD25highFoxP3+ regulatory T cells when cocultured with nonactivated peripheral blood T cells. Furthermore, when peripheral blood CD25high regulatory T cells (Tregs) were depleted from isolated CD3+ T cells, pericytes preferentially induced de novo formation of CD4+CD25highFoxP3+CD127-, suppressive regulatory T cells. Constitutive expression of PD-L1/2 and secretion of transforming growth factor-β 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.

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Human placental pericytes poorly stimulate and actively regulate allogeneic CD4 T cell responses.

Publications

Human placental pericytes poorly stimulate and actively regulate allogeneic CD4 T cell responses.

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