Pathological conversion of regulatory T cells is associated with loss of allotolerance

Hua, Jing; Inomata, Takenori; Chen, Yihe; Foulsham, William; Stevenson, William; Shiang, Tina; Bluestone, Jeffrey A.; Dana, Reza

doi:10.1038/s41598-018-25384-x

Cited by 82 publications

(79 citation statements)

References 56 publications

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“…However, systemic administration of immunosuppressive agents—such as rapamycin—cause patients to develop susceptibility to infection because these drugs also suppress healthy immune function needed to combat pathogens. One approach to prevent susceptibility to infection is by targeting the delivery of immunosuppressive drugs to activated T cells in proximity to the transplanted organ . Using hydrogels to reengineer the environment around the transplant site provides a means to probe how this local change alters the activity of graft‐reactive T cells.…”

Section: Biomaterials Enable Studies At the Interface Of Immune Cellsmentioning

confidence: 99%

Biomaterials as Tools to Decode Immunity

Eppler¹,

Jewell

2019

Advanced Materials

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The immune system has remarkable capabilities to combat disease with exquisite selectivity. This feature has enabled vaccines that provide protection for decades and, more recently, advances in immunotherapies that can cure some cancers. Greater control over how immune signals are presented, delivered, and processed will help drive even more powerful options that are also safe. Such advances will be underpinned by new tools that probe how immune signals are integrated by immune cells and tissues. Biomaterials are valuable resources to support this goal, offering robust, tunable properties. The growing role of biomaterials as tools to dissect immune function in fundamental and translational contexts is highlighted. These technologies can serve as tools to understand the immune system across molecular, cellular, and tissue length scales. A common theme is exploiting biomaterial features to rationally direct how specific immune cells or organs encounter a signal. This precision strategy, enabled by distinct material properties, allows isolation of immunological parameters or processes in a way that is challenging with conventional approaches. The utility of these capabilities is demonstrated through examples in vaccines for infectious disease and cancer immunotherapy, as well as settings of immune regulation that include autoimmunity and transplantation.

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Section: Biomaterials Enable Studies At the Interface Of Immune Cellsmentioning

confidence: 99%

Biomaterials as Tools to Decode Immunity

Eppler¹,

Jewell

2019

Advanced Materials

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“…In reverse, Treg cells can alter their phenotype and functions to adopt a Th17‐like effector cell profile too. It is important to understand these alterations as they can impact the regulatory balance in the graft . A further limitation is that much of our understanding to date originates from in vitro experiments and in vivo murine (or non‐human primate; NHP or swine) models .…”

Section: Introductionmentioning

confidence: 99%

Regulatory T cells in solid organ transplantation

et al. 2020

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The induction of graft tolerance remains the holy grail of transplantation. This is important as chronic allograft dysfunction and the side effects of immunosuppression regimens place a major burden on the lives of transplant patients and their healthcare systems. This has mandated the need to understand the immunobiology of graft rejection and identify novel therapeutics. Regulatory T (Treg) cells play an important role in modulating pro‐inflammatory microenvironments and maintaining tissue homeostasis. However, there are fundamental unanswered questions regarding Treg cell immunobiology. These cells are a heterogeneous entity with functionally diverse roles. Moreover, the adoption of novel deeper immunophenotyping and genomic sequencing technologies has identified this phenotype and function to be more complex than expected. Hence, a comprehensive understanding of Treg cell heterogeneity is needed to safely and effectively exploit their therapeutic potential. From a clinical perspective, the recent decade has seen different clinical teams commence and complete first‐in‐man clinical trials utilising Treg cells as an adoptive cellular therapy. In this review, we discuss these trials from a translational perspective with an important focus on safety. Finally, we identify crucial knowledge gaps for future study.

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“…9,10 Substantial progress has been made in determining the mechanisms by which host factors, such as recipient bed vascularity and inflammation, influence the immune response to corneal allografts. 16 Studies performed by our laboratory [17][18][19][20][21][22][23][24] and others [25][26][27] indicate the critical contribution of Foxp3 + Tregs to immune tolerance in the setting of corneal transplantation. 16 Studies performed by our laboratory [17][18][19][20][21][22][23][24] and others [25][26][27] indicate the critical contribution of Foxp3 + Tregs to immune tolerance in the setting of corneal transplantation.…”

Section: Introductionmentioning

confidence: 99%

“…17,[28][29][30] In the setting of corneal transplantation, we have demonstrated that Tregs derived from mice with inflamed and vascularized host beds that are prone to quick rejection (ie, high-risk hosts) have decreased expression of Foxp3 (the transcription factor that is crucial for their development and function) relative to low-risk hosts that survive long term. 17,[28][29][30] In the setting of corneal transplantation, we have demonstrated that Tregs derived from mice with inflamed and vascularized host beds that are prone to quick rejection (ie, high-risk hosts) have decreased expression of Foxp3 (the transcription factor that is crucial for their development and function) relative to low-risk hosts that survive long term.…”

Section: Introductionmentioning

confidence: 99%

“…17,[28][29][30] In the setting of corneal transplantation, we have demonstrated that Tregs derived from mice with inflamed and vascularized host beds that are prone to quick rejection (ie, high-risk hosts) have decreased expression of Foxp3 (the transcription factor that is crucial for their development and function) relative to low-risk hosts that survive long term. 17,23 The mechanisms by which Tregs exert their immunosuppressive effects remain an area of intense investigation. 17,23 The mechanisms by which Tregs exert their immunosuppressive effects remain an area of intense investigation.…”

Section: Introductionmentioning

confidence: 99%

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Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10

Coco

Foulsham

Yin

et al. 2020

American Journal of Transplantation

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| INTRODUC TI ONCorneal transplantation is the most common form of tissue grafting worldwide. 1 When performed on an uninflamed and nonvascularized host bed, the graft survival rate exceeds 90%. 2 However, inflammation and vascularization of the host bed disrupt the cornea's relatively tolerant immune microenvironment, and graft survival rates fall to ≈50% despite maximum immunosuppression in highrisk recipients. 3-5 Immune rejection is the leading cause of corneal graft failure. 6 Corneal endothelial cells (CEnCs) are the target of the effector immune response mediated primarily by graft-targeting CD4 + interferon gamma (IFNγ + ) T helper type 1 (Th1) cells. 7,8 When the CEnC count decreases beyond a certain threshold, they are no longer capable of maintaining corneal graft transparency and the graft fails. 9,10 Substantial progress has been made in determining the mechanisms by which host factors, such as recipient bed vascularity and inflammation, influence the immune response to corneal allografts. 11-15 Forkhead box protein 3 (Foxp3)-positive regulatory T cells (Tregs) are a subset of CD4 + T cells that play a critical role in maintaining immune tolerance. 16 Studies performed by our laboratory 17-24 and others 25-27 indicate the critical contribution of Foxp3 + Tregs to immune tolerance in the setting of corneal transplantation.The functional competence of corneal endothelial cells (CEnCs) is critical for survival of corneal allografts, but these cells are often targets of the immune response mediated by graft-attacking effector T cells. Although regulatory T cells (Tregs) have been studied for their role in regulating the host's alloimmune response towards the graft, the cytoprotective function of these cells on CEnCs has not been investigated. The aim of this study was to determine whether Tregs suppress effector T cell-mediated and inflammatory cytokine-induced CEnC death, and to elucidate the mechanism by which this cytoprotection occurs. Using 2 well-established models of corneal transplantation (low-risk and high-risk models), we show that Tregs derived from low-risk graft recipients have a superior capacity in protecting CEnCs against effector T cellmediated and interferon-γ and tumor necrosis factor-α-induced cell death compared to Tregs derived from high-risk hosts. We further demonstrate that the cytoprotective function of Tregs derived from low-risk hosts occurs independently of direct cell-cell contact and is mediated by the immunoregulatory cytokine IL-10. Our study is the first to report that Tregs provide cytoprotection for CEnCs through secretion of IL-10, indicating potentially novel therapeutic targets for enhancing CEnC survival following corneal transplantation. K E Y W O R D Sanimal models: murine, basic (laboratory) research/science, corneal transplantation/ ophthalmology, immune regulation, T cell biology, tolerance

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Pathological conversion of regulatory T cells is associated with loss of allotolerance

Cited by 82 publications

References 56 publications

Biomaterials as Tools to Decode Immunity

Biomaterials as Tools to Decode Immunity

Regulatory T cells in solid organ transplantation

Regulatory T cells promote corneal endothelial cell survival following transplantation via interleukin-10

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