The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation

Kraus, Anna; Chen, Jin; Edenhofer, Ilka; Ravens, Inga; Gaspert, Ariana; Cippà, Pietro E; Mueller, Steffen; Wüthrich, Rudolf P.; Segerer, Stephan; Bernhardt, Günter; Fehr, Thomas

doi:10.1371/journal.pone.0147951

Cited by 11 publications

(13 citation statements)

References 36 publications

(52 reference statements)

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“…In a previous study, Pfeiffer's team showed that blockade of CD155 resulted in decreased lysis of human hepatoblastoma cells ( 51 ), while Baofu's group demonstrated that blocking CD155 could enhance the proliferation of healthy CIK cells ( 52 ). In addition, Kraus' team found that the absence of CD112 or CD155 in kidney allografts did not significantly influence renal function ( 53 ). These discordant results may be attributable to CD155 biological function, which can combine with either TIGIT or CD226; hence, the results of CD155 blockage may be influenced by the ratio of TIGIT to CD226 expression levels.…”

Section: Discussionmentioning

confidence: 99%

Expression of the Inhibitory Receptor TIGIT Is Up-Regulated Specifically on NK Cells With CD226 Activating Receptor From HIV-Infected Individuals

et al. 2018

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Natural killer (NK) cells are important for maintenance of innate immune system stability and serve as a first line of defense against tumors and virus infections; they can act either directly or indirectly and are regulated via co-operation between inhibitory and stimulatory surface receptors. The recently reported inhibitory receptor, TIGIT, can be expressed on the NK cell surface; however, the expression level and function of TIGIT on NK cells during HIV infection is unknown. In this study, for the first time, we investigated the expression and function of TIGIT in NK cells from HIV-infected individuals. Our data demonstrate that the level of TIGIT is higher on NK cells from patients infected with human immunodeficiency virus (HIV) compared with HIV-negative healthy controls. TIGIT expression is inversely correlated with CD4+ T cell counts and positively correlated with plasma viral loads. Additionally, levels of the TIGIT ligand, CD155, were higher on CD4+ T cells from HIV-infected individuals compared with those from healthy controls; however, there was no difference in the level of the activating receptor, CD226, which recognizes the same ligands as TIGIT. Furthermore, TIGIT was found to specifically up-regulated on CD226+ NK cells in HIV-infected individuals, and either rIL-10, or rIL-12 + rIL-15, could induce TIGIT expression on these cells. In addition, high TIGIT expression inhibited the production of interferon-gamma (IFN-γ) by NK cells, while TIGIT inhibition restored IFN-γ production. Overall, these results highlight the important role of TIGIT in NK cell function and suggest a potential new avenue for the development of therapeutic strategies toward a functional cure for HIV.

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Section: Discussionmentioning

confidence: 99%

Expression of the Inhibitory Receptor TIGIT Is Up-Regulated Specifically on NK Cells With CD226 Activating Receptor From HIV-Infected Individuals

et al. 2018

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“…24,25 Furthermore, following activation of innate and adaptive immune pathways, DSA could trigger additional infiltration of T cells and development of a mixed rejection type (ABMR/T-cell-mediated rejection [TCMR]). 27,28 To both ligands, back signaling capacities have been attributed. 27,28 To both ligands, back signaling capacities have been attributed.…”

Section: Introductionmentioning

confidence: 99%

“…26 Besides HLA class I, PTEC express other T/NK cell receptor ligands that may be involved in rejection, eg, CD155 and CD166. 27,28 To both ligands, back signaling capacities have been attributed.…”

Section: Introductionmentioning

confidence: 99%

Back signaling of HLA class I molecules and T/NK cell receptor ligands in epithelial cells reflects the rejection-specific microenvironment in renal allograft biopsies

Egelkamp

Chichelnitskiy

Kühne

et al. 2019

American Journal of Transplantation

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The role of endothelial cells in the pathophysiology of antibody-mediated rejection after renal transplantation has been widely investigated. We expand this scenario to the impact of epithelial cells on the microenvironment during rejection. Primary proximal tubular epithelial cells were stimulated via HLA class I, CD155 and CD166based on their potential signal-transducing capacity to mediate back signaling after encounter with either T/NK cells or donor-specific antibodies. Upon crosslinking of these ligands with mAbs, PTEC secreted IL-6, CXCL1,8,10, CCL2, and sICAM-1.These proteins were also released by PTEC as consequence of a direct interaction with T/NK cells. Downmodulation of the receptor CD226 on effector cells confirmed the involvement of this receptor/ligand pair in back signaling. In vivo, CD155 and CD166 expression was detectable in proximal and distal tubuli of renal transplant biopsies, respectively. The composition of the protein microenvironment in these biopsies showed a substantial overlap with the PTEC response. Cluster and principal component analyses of the microenvironment separated unsuspicious from rejection biopsies and, furthermore, ABMR, TCMR, and borderline rejection. In conclusion, our results provide evidence that epithelial cells may contribute to the rejection process and pave the way to a better understanding of the pathomechanisms of kidney allograft rejection. K E Y W O R D Sbasic (laboratory) research/science, biomarker, immune regulation, immunobiology, immunosuppression/immune modulation, kidney transplantation/nephrology, natural killer (NK) cells/NK receptors, rejection: antibody-mediated (ABMR), T cell biology | 2693 EGELKAMP Et AL.

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“…CD112 and CD155 are constitutively expressed on renal tubular cells and strongly up‐regulated in acutely rejected renal allografts . However, CD226 blockade or the absence of CD112 or CD155 in the kidney allograft is not effective for preventing transplant rejection; the role of CD226 and its ligands remain largely unknown.…”

Section: Introductionmentioning

confidence: 99%

“…CD112 and CD155 are constitutively expressed on renal tubular cells and strongly up-regulated in acutely rejected renal allografts. 18 However, CD226 blockade or the absence of CD112 or CD155 in the kidney allograft is not effective for preventing transplant rejection; the role of CD226 and its ligands remain largely unknown. Recently, Eqelkamp et al suggested that CD155, HLA class І, and CD166 on renal epithelial cells interact with CD226 on T/NK effector cells, which contributes to the rejection-specific microenvironment in renal allograft.…”

mentioning

confidence: 99%

CD226 deficiency on regulatory T cells aggravates renal fibrosis via up-regulation of Th2 cytokines through miR-340

Zhang

Liu

et al. 2019

Journal of Leukocyte Biology

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In this study, we observed that deletion of CD226 on regulatory T cells (Tregs) precedes renal fibrosis in a mouse unilateral ureteral obstruction (UUO) model. First, we generated Treg‐specific CD226 gene knockout mice (CD226fl/fl Foxp3YFP‐Cre). Next, CD226fl/fl Foxp3YFP‐Cre mice and Foxp3YFP‐Cre control mice were subjected to UUO surgery. Pathologic analysis and Sirius red and Masson's trichrome staining showed that the kidneys of CD226fl/fl Foxp3YFP‐Cre mice following UUO showed much more severe interstitial fibrosis than Foxp3YFP‐Cre control mice at days 10 and 20. Additionally, CD226fl/fl Foxp3YFP‐Cre mice showed increased fibronectin expression, as demonstrated by immunohistochemistry (IHC) staining. Although Treg cell‐restricted CD226 deficiency showed increased Foxp3+ expression, expression of the cell surface functional molecule CD103 was significantly reduced, indicating impaired homeostasis in the Tregs of CD226fl/fl Foxp3YFP‐Cre mice. To better understand CD226 function, RNA sequencing (RNA‐Seq) analysis was conducted in Tregs isolated from CD226fl/fl Foxp3YFP‐Cre and Foxp3YFP‐Cre mice. RNA‐Seq data showed that the helper T cell (Th) 2‐related cytokines IL‐4 and IL‐10 were significantly up‐regulated in CD226 deficient Tregs. In addition, mRNA analysis of kidney samples from the mice following UUO by qPCR also showed increased IL‐4 and IL‐10 expression in CD226fl/fl Foxp3YFP‐Cre mice, as well as elevated TGF‐β1 levels, indicating that CD226 deficiency in Tregs resulted in the acquisition of the ability to produce Th2 cytokines. Finally, we found that microRNA‐340 (miR‐340), which was down‐regulated in Tregs isolated from CD226fl/fl Foxp3YFP‐Cre mice, directly regulated IL‐4 gene expression in vitro. These data suggest that the promotion of CD226 signaling on Tregs is a therapeutic target for renal disease.

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The Role of T Cell Costimulation via DNAM-1 in Kidney Transplantation

Cited by 11 publications

References 36 publications

Expression of the Inhibitory Receptor TIGIT Is Up-Regulated Specifically on NK Cells With CD226 Activating Receptor From HIV-Infected Individuals

Expression of the Inhibitory Receptor TIGIT Is Up-Regulated Specifically on NK Cells With CD226 Activating Receptor From HIV-Infected Individuals

Back signaling of HLA class I molecules and T/NK cell receptor ligands in epithelial cells reflects the rejection-specific microenvironment in renal allograft biopsies

CD226 deficiency on regulatory T cells aggravates renal fibrosis via up-regulation of Th2 cytokines through miR-340

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