Neuropilin-1 in Transplantation Tolerance

Campos‐Mora, Mauricio; Morales, Rodrigo A.; Gajardo, Tania; Catalán, Diego; Pino‐Lagos, Karina

doi:10.3389/fimmu.2013.00405

Cited by 16 publications

(13 citation statements)

References 90 publications

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“…Evidence from both murine and clinical studies suggests that Nrp1 expression in CD4 + T cells may have an important role in the context of allograft rejection 27 . It has been reported that CD4 + Nrp1 + T cells transferred to ectopic heart‐allograft recipient mice extend survival time of the graft by inhibiting the production of pro‐inflammatory cytokines, enriching Foxp3 + Treg population and inducing anergy on effector T cells 29 .…”

Section: Discussionmentioning

confidence: 99%

“…Initially the expression of Nrp1 was detected on neurons, but later its presence on dendritic cells, B cells and T cells was also proved. 27 In order to study the dynamic of Nrp1 expression on T cells, we first analyzed the expression of Nrp1 on CD4 + and CD8 + T cells from the spleen, peripheral lymph nodes and thymus that were removed from intact wild-type (WT) C57Bl/6 mice. As shown in Figure 1a, Nrp1 expression is mostly found in approximately 15-20% of CD4 + T cells from the spleen and peripheral lymph nodes.…”

Section: Among T Cells Nrp1 Is Mainly Expressed On Tregsmentioning

confidence: 99%

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Neuropilin‐1⁺ regulatory T cells promote skin allograft survival and modulate effector CD4⁺ T cells phenotypic signature

et al. 2014

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During allograft rejection, several immune cell types, including dendritic cells, CD4(+) and CD8(+) T cells among others, recirculate between the graft and the nearest draining lymph node, resulting in immunity against the 'foreign' tissue. Regulatory CD4(+) T cells are critical for controlling the magnitude of the immune response and may act to promote or maintain tolerance. They are characterized by the expression of CD25 and Foxp3, and more recently, Neuropilin-1 (Nrp1). The role of these suppressor cells during allograft rejection is not well understood. Our work shows that during graft rejection, there is an increase in the frequency of total CD4(+) T cells expressing Nrp1, but the expression of this molecule is downregulated in the regulatory CD4(+) T-cell compartment. Interestingly, the expression of the transcription factor Eos, which renders cell function stability, is also reduced. In adoptive transfer experiments, we observed that during allograft rejection: (i) natural regulatory CD4(+) T cells maintain high levels of Nrp1 expression, (ii) effector CD4(+) T cells (Nrp1(-)) become Nrp1(+)Eos(+) and (iii) the transfer of regulatory CD4(+) T cells (Nrp1(+)) can promote allograft survival, and also enhance the gain of Nrp1 and Eos on T-effector cells. Together, these data suggest that rejection occurs, at least in part, through the loss of Nrp1 expression on regulatory CD4(+) T cells, their stability or both. Additionally, the transfer of regulatory CD4(+) T cells (based on Nrp1 expression) permits the acceptance of the allograft, placing Nrp1 as a new target for immune therapy.

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Section: Discussionmentioning

confidence: 99%

Section: Among T Cells Nrp1 Is Mainly Expressed On Tregsmentioning

confidence: 99%

Neuropilin‐1⁺ regulatory T cells promote skin allograft survival and modulate effector CD4⁺ T cells phenotypic signature

et al. 2014

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“…Ten days after transplantation, mice were sacrificed and their dLNs and spleens were harvested and assessed for the type and frequency of Tregs present. Among the main Treg subtypes, we investigated natural Tregs (nTregs), which are demarcated by surface CD4 + and Neuropilin-1 (Nrp1) expression, and expressed the transcription factor FoxP3 ( 27 – 29 ), pTregs that are CD4 + , FoxP3 + , Nrp1 − , or Nrp1 LO ( 29 , 30 ), and Tr1 T cells, which are CD4 + , FoxP3 − , CD25 − , CD49b + , Lag-3 + (CD223 + ), and express inducible T cell costimulatory (ICOS). In addition, these cells express higher latent-associated TGF-β and secrete IL-10 ( 27 , 31 ).…”

Section: Resultsmentioning

confidence: 99%

miR-466a Targeting of TGF-β2 Contributes to FoxP3+ Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation

Becker

Nagarkatti

2018

Front. Immunol.

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The promise of inducing immunological tolerance through regulatory T cell (Treg) control of effector T cell function is crucial for developing future therapeutic strategies to treat allograft rejection as well as inflammatory autoimmune diseases. In the current study, we used murine allograft rejection as a model to identify microRNA (miRNA) regulation of Treg differentiation from naïve CD4 cells. We performed miRNA expression array in CD4+ T cells in the draining lymph node (dLN) of mice which received syngeneic or allogeneic grafts to determine the molecular mechanisms that hinder the expansion of Tregs. We identified an increase in miRNA cluster 297-669 (C2MC) after allogeneic transplantation, in CD4+ T cells, such that 10 of the 27 upregulated miRNAs were all from this cluster, with one of its members, mmu-miR-466a-3p (miR-466a-3p), targeting transforming growth factor beta 2 (TGF-β2), as identified through reporter luciferase assay. Transfection of miR-466a-3p in CD4+ T cells led to a decreased inducible FoxP3+ Treg generation while inhibiting miR-466a-3p expression through locked nucleic acid resulting in increased Tregs and a reduction in effector T cells. Furthermore, in vivo inhibition of miR-466a-3p in an allogeneic skin-graft model attenuated T cell response against the graft through an increase in TGF-β2. TGF-β2 was as effective as TGF-β1 at both inducing Tregs and through adoptive transfer, mitigating host effector T cell response against the allograft. Together, the current study demonstrates for the first time a new role for miRNA-466a-3p and TGF-β2 in the regulation of Treg differentiation and thus offers novel avenues to control inflammatory disorders.

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“…However, another angiogenic factor regulated by IL-6, Nrp-1, was significantly suppressed in TP2 mice. Because Nrp-1 can also modulate regulatory T cell-mediated antigen recognition [ 48 , 49 ], VEGF-α and Nrp-1 in our system may be differentially regulated by IL-6 and the regulation of Nrp-1 by hpMSCs plays a role in hpMSC-mediated immune modulation. This is an intriguing quandary to be further studied.…”

Section: Discussionmentioning

confidence: 99%

Double-Injected Human Stem Cells Enhance Rehabilitation in TBI Mice Via Modulation of Survival and Inflammation

Kim¹,

Park

Kong

et al. 2017

Mol Neurobiol

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Traumatic brain injury (TBI), a complicated form of brain damage, is a major cause of mortality in adults. Following mechanical and structural primary insults, a battery of secondary insults, including neurotransmitter-mediated cytotoxicity, dysregulation of calcium and macromolecule homeostasis, and increased oxidative stress, exacerbate brain injury and functional deficits. Although stem cell therapy is considered to be an alternative treatment for brain injuries, such as TBI and stroke, many obstacles remain. In particular, the time window for TBI treatment with either drugs or stem cells and their efficacy is still vague. Human placenta-derived mesenchymal stem cells (hpMSCs) have received extensive attention in stem cell therapy because they can be acquired in large numbers without ethical issues and because of their immune-modulating capacity and effectiveness in several diseases, such as Alzheimer’s disease and stroke. Here, we tested the feasibility of hpMSCs for TBI treatment with an animal model and attempted to identify appropriate time points for cell treatments. Double injections at 4 and 24 h post-injury significantly reduced the infarct size and suppressed astrocyte and microglial activation around the injury. With reduced damage, double-injected mice showed enhanced anti-inflammatory- and TNF-α receptor 2 (TNFR2)-associated survival signals and suppressed pro-inflammatory and oxidative responses. In addition, double-treated TBI mice displayed restored sensory motor functions and reduced neurotoxic Aβ42 plaque formation around the damaged areas. In this study, we showed the extended therapeutic potentials of hpMSCs and concluded that treatment within an appropriate time window is critical for TBI recovery.

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Neuropilin-1 in Transplantation Tolerance

Cited by 16 publications

References 90 publications

Neuropilin‐1⁺ regulatory T cells promote skin allograft survival and modulate effector CD4⁺ T cells phenotypic signature

Neuropilin‐1⁺ regulatory T cells promote skin allograft survival and modulate effector CD4⁺ T cells phenotypic signature

miR-466a Targeting of TGF-β2 Contributes to FoxP3+ Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation

Double-Injected Human Stem Cells Enhance Rehabilitation in TBI Mice Via Modulation of Survival and Inflammation

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Neuropilin-1 in Transplantation Tolerance

Cited by 16 publications

References 90 publications

Neuropilin‐1+ regulatory T cells promote skin allograft survival and modulate effector CD4+ T cells phenotypic signature

Neuropilin‐1+ regulatory T cells promote skin allograft survival and modulate effector CD4+ T cells phenotypic signature

miR-466a Targeting of TGF-β2 Contributes to FoxP3+ Regulatory T Cell Differentiation in a Murine Model of Allogeneic Transplantation

Double-Injected Human Stem Cells Enhance Rehabilitation in TBI Mice Via Modulation of Survival and Inflammation

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Neuropilin‐1⁺ regulatory T cells promote skin allograft survival and modulate effector CD4⁺ T cells phenotypic signature

Neuropilin‐1⁺ regulatory T cells promote skin allograft survival and modulate effector CD4⁺ T cells phenotypic signature