Unexpected Acceleration of Type 1 Diabetes by Transgenic Expression of B7-H1 in NOD Mouse Peri-Islet Glia

Yantha, Jason; Tsui, Hubert; Winer, Shawn; Song, Aihua; Wu, Ping; Paltser, Geoff; Ellis, James; Dosch, H.-Michael

doi:10.2337/db09-1209

Cited by 16 publications

(12 citation statements)

References 40 publications

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“…In a model of diabetes, PD‐L1 expression was targeted to a second nonhematopoietic cell in the pancreas, the peri‐islet Schwann cell (pSC). PD‐L1 expression on pSC was achieved using the glial fibrillary acidic protein (GFAP) promoter 116 . pSC expression of PD‐L1 did not protect mice from developing diabetes 116 .…”

Section: Clinical Opportunities and Translational Applicationsmentioning

confidence: 99%

“…PD‐L1 expression on pSC was achieved using the glial fibrillary acidic protein (GFAP) promoter 116 . pSC expression of PD‐L1 did not protect mice from developing diabetes 116 . These failed attempts underscore the complexity of targeting costimulatory pathways in vivo to enhance islet‐specific tolerance, despite the critical role of PD‐L1 for tolerance maintenance.…”

Section: Clinical Opportunities and Translational Applicationsmentioning

confidence: 99%

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The role of the PD‐1 pathway in autoimmunity and peripheral tolerance

Fife

Pauken

2011

Annals of the New York Academy of Sciences

315

215

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Programmed death-1 (PD-1) is a surface receptor critical for the regulation of T cell function during immunity and tolerance. PD-1 interactions with its ligands PD-L1 and PD-L2 inhibit T cell effector functions in an antigen-specific manner. This paper examines the role of PD-1 in limiting autoreactivity and establishing self-tolerance and discusses the hypothesis that PD-1 ligand (PD-L) expression both spatially and temporally dictates the fate of self-reactive T cells during the breakdown of peripheral tolerance and development of autoimmunity. We focus our discussion on the role of PD-1/PD-L interactions during peripheral tolerance, the differential role for PD-L1 and PD-L2 in response to environmental or self-antigens, and the impact of PD-1 signaling on dynamic T cell motility and the T cell receptor (TCR) stop signal. Finally, we discuss the potential to selectively target the PD-1 pathway therapeutically to alter T cell function during autoimmunity.

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Section: Clinical Opportunities and Translational Applicationsmentioning

confidence: 99%

Section: Clinical Opportunities and Translational Applicationsmentioning

confidence: 99%

The role of the PD‐1 pathway in autoimmunity and peripheral tolerance

Fife

Pauken

2011

Annals of the New York Academy of Sciences

315

215

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“…Surprisingly however, there is also evidence that PD‐L1 expression on non‐immune cells (e.g. pancreatic islet β cells or peri‐islet glia) can promote allograft rejection 17 and autoimmunity 17, 18. Thus, the role of PD‐L1 may depend on the nature of the disease, the genetic background of the experimental model, the type of cells involved and the activation status of the T cells, with a need for stringent regulation of PD‐L1 expression.…”

Section: The Programmed Death Ligand‐1: Pd‐1 Pathway and Negative Regmentioning

confidence: 99%

The STATus of PD‐L1 (B7‐H1) on tolerogenic APCs

Sumpter

Thomson

2011

Eur J Immunol

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Expression by DCs of co-inhibitory molecules such as programmed death ligand-1 (PD-L1/ B7-H1/CD274), a member of the B7 superfamily, is crucial for the downregulation of T-cell responses and the maintenance of immune homeostasis. Exposure of immature DCs to danger-associated molecular patterns (DAMPS) or pathogen-associated molecular patterns (PAMPs) generally results in their maturation and acquisition of immunostimulatory function. However, exposure of DCs to TLR ligands early during their differentiation can inhibit further differentiation and confer tolerogenic properties on these APCs. A report in this issue of The European Journal of Immunology reveals that early inhibition of human DC differentiation from blood monocytes by TLR agonists is associated with a tolerogenic phenotype and Treg generation. The tolerogenic function of these APCs is dependent on MAPK-induced IL-6 and IL-10 production, which drives STAT-3-mediated PD-L1 expression. These observations link IL-10 and IL-6 to PD-L1 expression, providing a new dimension to the anti-inflammatory properties of these cytokines. These findings also have implications for understanding the inherent function of DCs in non-lymphoid tissues such as the liver and lung, where they are exposed to PAMPs that are found constitutively in the local microenvironment. Keywords: DC . PD-L1 (B7-H1) . STAT-3 . ToleranceSee accompanying article by Wölfle et al. The programmed death ligand-1: PD-1 pathway and negative regulation of immune responsesDCs are highly proficient APCs that orchestrate innate and adaptive immune responses [1]. Interstitial DCs in peripheral tissues are considered 'immature' since they express low levels of surface MHC class II and co-stimulatory molecules. Following encounter with danger-associated molecular patterns (DAMPs), or pathogen-associated molecular patterns (PAMPs) such as LPS and other TLR ligands, DCs mature by up-regulating surface MHC class II and co-stimulatory molecules, as well as co-regulatory molecules, such as the B7-CD28 superfamily member, programmed death ligand-1 (PD-L1/B7-H1/CD274) [2]. The balance between the level of expression of co-stimulatory relative to co-regulatory molecules at the APC surface is a crucial determinant of the outcome of DC-T cell interaction -higher relative expression of co-stimulatory molecules is predictive of T-cell activation, while higher expression of co-regulatory molecules, particularly PD-L1, correlates with negative immune regulation [3,4].In general terms, the interaction between PD-L1 and its receptor, PD-1, inhibits immune cell activation [5]. Both PD-L1 and PD-1 are type-I transmembrane Ig-superfamily members.

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“…They found that the peri-islet lymphocytic accumulation in insulitis creates disturbances and breaches of the glial sheath prior to the autoimmune attack on the beta cells [14][15][16]. Interestingly, in contrast to the destruction of Schwann cells, reactive gliosis was also reported in streptozotocin (STZ)-injected mice [17].…”

Section: Introductionmentioning

confidence: 99%

Plasticity of Schwann cells and pericytes in response to islet injury in mice

et al. 2013

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Aims/hypothesis Islet Schwann (glial) cells and pericytes are the microorgan's accessory cells positioned at the external and internal boundaries facing the exocrine pancreas and endothelium, respectively, adjacent to the endocrine cells. Plasticity of glial cells and pericytes is shown in the glial scar formation after injury to the central nervous system. It remains unclear whether similar reactive cellular responses occur in insulitis. We applied three-dimensional (3D) histology to perform qualitative and quantitative analyses of the islet Schwann cell network and pericytes in normal, streptozotocin-injected (positive control of gliosis) and NOD mouse models. Methods Vessel painting paired with immunostaining of mouse pancreatic tissue was used to reveal the islet Schwann cells and pericytes and their association with vasculature. Transparent islet specimens were prepared by optical clearing to facilitate 3D confocal microscopy for panoramic visualisation of the tissue networks.Results In-depth microscopy showed that the islet Schwann cell network extends from the peri-islet domain into the core. One week after streptozotocin injection, we observed intraislet perivascular gliosis and an increase in pericyte density. In early/moderate insulitis in the NOD mice, perilesional gliosis occurred at the front of the lymphocytic infiltration with atypical islet Schwann cell morphologies, including excessive branching and perivascular gliosis. Meanwhile, pericytes aggregated on the walls of the feeding arteriole at the peri-and intralesional domains with a marked increase in surface marker density. Conclusions/interpretationThe reactive cellular responses demonstrate plasticity and suggest a stop-gap mechanism consisting of the Schwann cells and pericytes in association with the islet lesion and vasculature when injury occurs.

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Unexpected Acceleration of Type 1 Diabetes by Transgenic Expression of B7-H1 in NOD Mouse Peri-Islet Glia

Cited by 16 publications

References 40 publications

The role of the PD‐1 pathway in autoimmunity and peripheral tolerance

The role of the PD‐1 pathway in autoimmunity and peripheral tolerance

The STATus of PD‐L1 (B7‐H1) on tolerogenic APCs

Plasticity of Schwann cells and pericytes in response to islet injury in mice

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