Maintaining T cell tolerance of alloantigens: Lessons from animal studies

Robinson, Kortney; Orent, William; Madsen, Joren C.; Bénichou, Gilles

doi:10.1111/ajt.14984

Cited by 6 publications

(4 citation statements)

References 194 publications

(377 reference statements)

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“…The PD-1/PD-L1 is also predicted to be activated in pre-cDC1s compared to CD8α+ cDC1s, which would be highly beneficial for induction of tolerance in the HCT setting. Interestingly, while PD-1 signaling is critical to induction and maintenance of peripheral tolerance in transplantation, the induction of programmed cell death of alloreactive T-cells has been specifically linked to PD-L1, and its ligand is not believed to be PD-1 [ 53 – 57 ].…”

Section: Discussionmentioning

confidence: 99%

Murine precursors to type 1 conventional dendritic cells induce tumor cytotoxicity and exhibit activated PD-1/PD-L1 pathway

Molina

Hoffman²,

Stokes³

et al. 2022

PLoS ONE

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The immediate precursor to murine type 1 conventional DCs (cDC1s) has recently been established and named “pre-cDC1s”. Mature CD8α+ cDC1s are recognized for suppressing graft-versus-host disease (GvHD) while promoting graft-versus-leukemia (GvL), however pre-cDC1s have not previously been investigated in the context of alloreactivity or anti-tumor responses. Characterization of pre-cDC1s, compared to CD8α+ cDC1s, found that a lower percentage of pre-cDC1s express PD-L1, yet express greater PD-L1 by MFI and a greater percent PIR-B, a GvHD-suppressing molecule. Functional assays were performed ex vivo following in vivo depletion of CD8α+ DCs to examine whether pre-cDC1s play a redundant role in alloreactivity. Proliferation assays revealed less allogeneic T-cell proliferation in the absence of CD8α+ cDC1s, with slightly greater CD8+ T-cell proliferation. Further, in the absence of CD8α+ cDC1s, stimulated CD8+ T-cells exhibited significantly less PD-1 expression compared to CD4+ T-cells, and alloreactive T-cell death was significantly lower, driven by reduced CD4+ T-cell death. Tumor-killing assays revealed that T-cells primed with CD8α-depleted DCs ex vivo induce greater killing of A20 B-cell leukemia cells, particularly when antigen (Ag) is limited. Bulk RNA sequencing revealed distinct transcriptional programs of these DCs, with pre-cDC1s exhibiting activated PD-1/PD-L1 signaling compared to CD8α+ cDC1s. These results indicate distinct T-cell-priming capabilities of murine pre-cDC1s compared to CD8α+ cDC1s ex vivo, with potentially clinically relevant implications in suppressing GvHD while promoting GvL responses, highlighting the need for greater investigation of murine pre-cDC1s.

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Section: Discussionmentioning

confidence: 99%

Murine precursors to type 1 conventional dendritic cells induce tumor cytotoxicity and exhibit activated PD-1/PD-L1 pathway

Molina

Hoffman²,

Stokes³

et al. 2022

PLoS ONE

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“…T-cells stimulated with 100μM BEN-exposed FL-BMDCs exhibited a striking increase in PD-1 expression and accelerated proliferation, followed by activation-induced death of half of all allogeneic T-cells in culture. The induction of programmed cell death of alloreactive T-cells has been specifically linked to PD-L1 ( 63 ) and is critical to induction and maintenance of peripheral tolerance in transplantation ( 64 – 67 ). It is also worth noting that our previous study found that DCs isolated from BEN-treated mice induced less allogeneic T-cell proliferation compared to CY-treated mice.…”

Section: Discussionmentioning

confidence: 99%

Regulatory Dendritic Cells Induced by Bendamustine Are Associated With Enhanced Flt3 Expression and Alloreactive T-Cell Death

et al. 2021

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The growth factor Flt3 ligand (Flt3L) is central to dendritic cell (DC) homeostasis and development, controlling survival and expansion by binding to Flt3 receptor tyrosine kinase on the surface of DCs. In the context of hematopoietic cell transplantation, Flt3L has been found to suppress graft-versus-host disease (GvHD), specifically via host DCs. We previously reported that the pre-transplant conditioning regimen consisting of bendamustine (BEN) and total body irradiation (TBI) results in significantly reduced GvHD compared to cyclophosphamide (CY)+TBI. Pre-transplant BEN+TBI conditioning was also associated with greater Flt3 expression among host DCs and an accumulation of pre-cDC1s. Here, we demonstrate that exposure to BEN increases Flt3 expression on both murine bone marrow-derived DCs (BMDCs) and human monocyte-derived DCs (moDCs). BEN favors development of murine plasmacytoid DCs, pre-cDC1s, and cDC2s. While humans do not have an identifiable equivalent to murine pre-cDC1s, exposure to BEN resulted in decreased plasmacytoid DCs and increased cDC2s. BEN exposure and heightened Flt3 signaling are associated with a distinct regulatory phenotype, with increased PD-L1 expression and decreased ICOS-L expression. BMDCs exposed to BEN exhibit diminished pro-inflammatory cytokine response to LPS and induce robust proliferation of alloreactive T-cells. These proliferative alloreactive T-cells expressed greater levels of PD-1 and underwent increased programmed cell death as the concentration of BEN exposure increased. Alloreactive CD4+ T-cell death may be attributable to pre-cDC1s and provides a potential mechanism by which BEN+TBI conditioning limits GvHD and yields T-cells tolerant to host antigen.

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“…However, studies have also found that Kupffer cells can induce Tregs to proliferate and secrete IL-10 through direct contact with Tregs while inhibiting T cell activation by secreting PGE2 and 15d-PGJ2 (31)(32)(33)(34). Sinusoidal endothelial cells, as the main components of liver non-parenchymal cells, can induce T cell apoptosis by inducing the expression of PD-L1 and inhibiting T cell secretion of IL-2, thereby inducing immune tolerance (35,36). Meanwhile, studies have shown that hepatic sinusoidal endothelial cells can induce CD4 + T cells to differentiate into CD4 + CD25 low Foxp3specific T cell subsets with inhibitory activity (37).…”

Section: The Immunologic Characteristics Of Livermentioning

confidence: 99%

Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation

Wang

et al. 2021

Front. Immunol.

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Rejection after organ transplantation is a cause of graft failure. Effectively reducing rejection and inducing tolerance is a challenge in the field of transplantation immunology. The liver, as an immunologically privileged organ, has high rates of spontaneous and operational tolerance after transplantation, allowing it to maintain its normal function for long periods. Although modern immunosuppression regimens have serious toxicity and side effects, it is very risky to discontinue immunosuppression regimens blindly. A more effective treatment to induce immune tolerance is the most sought-after goal in transplant medicine. Tregs have been shown to play a pivotal role in the regulation of immune balance, and infusion of Tregs can also effectively prevent rejection and cure autoimmune diseases without significant side effects. Given the immune characteristics of the liver, the correct use of Tregs can more effectively induce the occurrence of operational tolerance for liver transplants than for other organ transplants. This review mainly summarizes the latest research advances regarding the characteristics of the hepatic immune microenvironment, operational tolerance, Treg generation in vitro, and the application of Tregs in liver transplantation. It is hoped that this review will provide a deeper understanding of Tregs as the most effective treatment to induce and maintain operational tolerance after liver transplantation.

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Maintaining T cell tolerance of alloantigens: Lessons from animal studies

Cited by 6 publications

References 194 publications

Murine precursors to type 1 conventional dendritic cells induce tumor cytotoxicity and exhibit activated PD-1/PD-L1 pathway

Murine precursors to type 1 conventional dendritic cells induce tumor cytotoxicity and exhibit activated PD-1/PD-L1 pathway

Regulatory Dendritic Cells Induced by Bendamustine Are Associated With Enhanced Flt3 Expression and Alloreactive T-Cell Death

Clinical and Basic Research Progress on Treg-Induced Immune Tolerance in Liver Transplantation

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