Targeting CD8 T-Cell Metabolism in Transplantation

Yap, Michelle; Brouard, Sophie; Pecqueur, Claire; Degauque, Nicolas

doi:10.3389/fimmu.2015.00547

Cited by 18 publications

(17 citation statements)

References 90 publications

(92 reference statements)

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“…Kidney transplantation will activate the recipient’s immune system accompanied by an increase in cytokine production, including production of the pro-inflammatory IFNγ [35, 39, 40], and upregulation of PD1 expression [41]. As protein expression inversely correlates with DNA methylation levels at gene promoter sites, kidney transplantation induces demethylation of genes involved in immune activation.…”

Section: Discussionmentioning

confidence: 99%

“…Graft-infiltrating cytotoxic CD8+ T cells play a major role in the rejection process and elevated numbers of effector, and memory CD8+ T cell subsets are associated with an increased risk for acute rejection [33–35]. Here, we examined the influence of variations in DNA methylation of IFNγ and PD1 in different CD8+ T cell subsets on allograft rejection.…”

Section: Introductionmentioning

confidence: 99%

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Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

et al. 2016

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BackgroundThe role of DNA methylation in the regulation of the anti-donor-directed immune response after organ transplantation is unknown. Here, we studied the methylation of two mediators of the immune response: the pro-inflammatory cytokine interferon γ (IFNγ) and the inhibitory receptor programmed death 1 (PD1) in naïve and memory CD8+ T cell subsets in kidney transplant recipients receiving immunosuppressive medication. Both recipients experiencing an episode of acute allograft rejection (rejectors) as well as recipients without rejection (non-rejectors) were included.ResultsCpGs in the promoter regions of both IFNγ and PD1 were significantly (p < 0.001) higher methylated in the naïve CD8+ T cells compared to the memory T cell subsets. The methylation status of both IFNγ and PD1 inversely correlated with the percentage of IFNγ or PD1-producing cells. Before transplantation, the methylation status of both IFNγ and PD1 was not significantly different from healthy donors. At 3 months after transplantation, irrespective of rejection and subsequent anti-rejection therapy, the IFNy methylation was significantly higher in the differentiated effector memory CD45RA+ (EMRA) CD8+ T cells (p = 0.01) whereas the PD1 methylation was significantly higher in all memory CD8+ T cell subsets (CD27+ memory; p = 0.02: CD27− memory; p = 0.02: EMRA; p = 0.002). Comparing the increase in methylation in the first 3 months after transplantation between rejectors and non-rejectors demonstrated a significantly more prominent increase in the PD1 methylation in the CD27− memory CD8+ T cells in rejectors (increase in rejectors 14%, increase in non-rejectors 1.9%, p = 0.04). The increase in DNA methylation in the other memory CD8+ T cells was not significantly different between rejectors and non-rejectors. At 12 months after transplantation, the methylation of both IFNγ and PD1 returned to baseline levels.ConclusionsThe DNA methylation of both IFNγ and PD1 increases the first 3 months after transplantation in memory CD8+ T cells in kidney transplant recipients. This increase was irrespective of a rejection episode indicating that general factors of the kidney transplantation procedure, including the use of immunosuppressive medication, contribute to these variations in DNA methylation.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

et al. 2016

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“…Mismatches in the MHC correlate negatively with long‐term graft survival in solid organ transplantation due to the reactivity of donor‐reactive anti‐HLA antibodies . In addition, the incompatibility of MHC between donor and recipient activates donor‐reactive T cells, especially from the CD8 + subset, which in turn trigger acute inflammation and destruction of the grafted organ by recognizing donor MHC class I molecules . Accordingly, several concepts are currently being tested to achieve immune protection of allogeneic cells by reducing or deleting MHC class I expression …”

Section: Introductionmentioning

confidence: 99%

“…15,16 In addition, the incompatibility of MHC between donor and recipient activates donor-reactive T cells, especially from the CD8 + subset, which in turn trigger acute inflammation and destruction of the grafted organ by recognizing donor MHC class I molecules. 17,18 Accordingly, several concepts are currently being tested to achieve immune protection of allogeneic cells by reducing or deleting MHC class I expression. 19,20 As in alloreactivity, MHC molecules (swine leukocyte antigen [SLA]) of the porcine donor trigger the recipient's T cell responses after xenotransplantation.…”

Section: Introductionmentioning

confidence: 99%

Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype—Effects on immune status and susceptibility to human immune responses

Hein

Sake

Pokoyski

et al. 2020

American Journal of Transplantation

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Porcine xenografts lacking swine leukocyte antigen (SLA) class I are thought to be protected from human T cell responses. We have previously shown that SLA class I deficiency can be achieved in pigs by CRISPR/Cas9‐mediated deletion of β2‐microglobulin (B2M). Here, we characterized another line of genetically modified pigs in which targeting of the B2M locus did not result in complete absence of B2M and SLA class I but rather in significantly reduced expression levels of both molecules. Residual SLA class I was functionally inert, because no proper differentiation of the CD8+ T cell subset was observed in B2Mlow pigs. Cells from B2Mlow pigs were less capable in triggering proliferation of human peripheral blood mononuclear cells in vitro, which was mainly due to the nonresponsiveness of CD8+ T cells. Nevertheless, cytotoxic effector cells developing from unaffected cell populations (eg, CD4+ T cells, natural killer cells) lysed targets from both SLA class I+ wildtype and SLA class Ilow pigs with similar efficiency. These data indicate that the absence of SLA class I is an effective approach to prevent the activation of human CD8+ T cells during the induction phase of an anti‐xenograft response. However, cytotoxic activity of cells during the effector phase cannot be controlled by this approach.

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“…The lung has both low cellularity and a low glycolytic rate, whereas immune cells have high aerobic glycolysis . Importantly, both activated CD8+ cells and neutrophils have high aerobic glycolysis, so an increased lactate and LtP could be attributed to either source; a combination of both mechanisms likely produces the contrast observed in our imaging technique.…”

Section: Discussionmentioning

confidence: 96%

Detection of lung transplant rejection in a rat model using hyperpolarized [1‐¹³C] pyruvate‐based metabolic imaging

et al. 2019

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The current standard for noninvasive imaging of acute rejection consists of X-ray/CT, which derive their contrast from changes in ventilation, inflammation and edema, as well as remodeling during rejection. We propose the use of hyperpolarized [1-13 C] pyruvate MRI-which provides real-time metabolic assessment of tissue-as an early biomarker for tissue rejection.In this preliminary study, we used μCT-derived parameters and HP 13 C MR-derived biomarkers to predict rejection in an orthotopic left lung transplant model in both allogeneic and syngeneic rats.On day 3, the normalized lung density-a parameter that accounts for both lung volume (mL) and density (HU)-was −0.335 (CI: -0.598, −0.073) and − 0.473 (CI: -0.726, −0.220) for the allograft and isograft, respectively (not significant, 0.40). The lactate-to-pyruvate ratios-derived from the HP 13 C MRI-for the allograft and isograft were 0.200 (CI: 0.161, 0.240) and 0.114 (CI: 0.074, 0.153), respectively (significant, 0.020). Both techniques showed tissue rejection on day 7. A separate sub-study revealed CD8+ cells as the primary source of the lactate-to-pyruvate signal.Our study suggests that hyperpolarized (HP) [1-13 C] pyruvate MRI is a promising early biomarker for tissue rejection that provides metabolic assessment in real time based on changes in cellularity and metabolism of lung tissue and the infiltrating inflammatory cells, and may be able to predict tissue rejection earlier than X-ray/CT.

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Targeting CD8 T-Cell Metabolism in Transplantation

Cited by 18 publications

References 90 publications

Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype—Effects on immune status and susceptibility to human immune responses

Detection of lung transplant rejection in a rat model using hyperpolarized [1‐¹³C] pyruvate‐based metabolic imaging

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Targeting CD8 T-Cell Metabolism in Transplantation

Cited by 18 publications

References 90 publications

Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

Variations in DNA methylation of interferon gamma and programmed death 1 in allograft rejection after kidney transplantation

Triple (GGTA1, CMAH, B2M) modified pigs expressing an SLA class Ilow phenotype—Effects on immune status and susceptibility to human immune responses

Detection of lung transplant rejection in a rat model using hyperpolarized [1‐13C] pyruvate‐based metabolic imaging

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Detection of lung transplant rejection in a rat model using hyperpolarized [1‐¹³C] pyruvate‐based metabolic imaging