Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production

Daszkiewicz, Lidia; Vázquez-Mateo, Cristina; Rackov, Gorjana; Ballesteros-Tato, André; Weber, Kathrin; Madrigal-Avilés, Adrián; Pilato, Mauro Di; Fotedar, Arun; Fotedar, Rati; Flores, Juana M.; Esteban, Mariano; Martı́nez-A, Carlos; Balomenos, Dimitrios

doi:10.1038/srep07691

Cited by 26 publications

(24 citation statements)

References 55 publications

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“…Downregulation of interferon‐ γ may be related to higher p21 levels in the hyperoxia group at 3 months, as overexpressed p21 reduces T‐cell activation and interferon‐ γ secretion (Daszkiewicz et al. ). CD40–CD40 ligand interactions are critical for development of CD4 T‐cell‐dependent effector functions.…”

Section: Discussionmentioning

confidence: 99%

“…Recovery from severe suppression of immune genes following hyperoxia may be prolonged and dysfunctional in adult mice. Downregulation of interferon-c may be related to higher p21 levels in the hyperoxia group at 3 months, as overexpressed p21 reduces T-cell activation and interferon-c secretion (Daszkiewicz et al 2015). CD40-CD40 ligand interactions are critical for development of CD4 T-cell-dependent effector functions.…”

Section: Discussionmentioning

confidence: 99%

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Adaptive immune responses are altered in adult mice following neonatal hyperoxia

2018

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Premature infants with bronchopulmonary dysplasia (BPD), are at risk for frequent respiratory infections and reduced pulmonary function. We studied whether neonatal hyperoxia disrupts adaptive immune responses in adult mice, contributing to higher respiratory‐related morbidities seen in these infants. Newborn mice litters were randomized at 3 days to 85% O2 or room air (RA) for 12 days. Whole lung mRNA was isolated in both the groups at 2 weeks and 3 months. Gene expression for T‐cell and B‐cell adaptive immune response was performed by real‐time PCR and qRT‐PCR; protein expression (p21, IL4, IL10, IL27, cd4) was performed by enzyme immunoassay along with p21 immunohistochemistry. Hyperoxia increased expression of p21 and decreased expression of 19 genes representing T/B‐cell activation by ≥ fourfold; three of them significantly (Rag1, Cd1d1, Cd28) compared to the RA group at 2 weeks. Despite RA recovery, the expression of IFN γ, IL27, and CD40 was significantly reduced at 3 months in the hyperoxia group. Expression of p21 was significantly higher and IL27 protein lower at 2 weeks following hyperoxia. Adult mice exposed to neonatal hyperoxia had lower IL4 and IL10 in the lung at 3 months. Adaptive immune responses are developmentally regulated and neonatal hyperoxia suppresses expression of genes involved in T‐/B‐cell activation with continued alterations in gene expression at 3 months. Dysfunction of adaptive immune responses increases the risk for susceptibility to infection in premature infants.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Adaptive immune responses are altered in adult mice following neonatal hyperoxia

2018

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“…In those studies, it was reported that the therapeutic mechanism, although mediated by death ligands, did not involve apoptosis. This could be probably due to cell cycle inhibition mediated by the induction of p21 expression in activated T cells by exosome-bound FasL and/or TRAIL [115,116,117]. This mechanism is also influencing the pathogenesis of autoimmune lymphoproliferative syndromes due to mutations in Fas or FasL and should be kept in mind for their treatment [115].…”

Section: Exosomes In Autoimmune and Chronic Inflammatory Diseasesmentioning

confidence: 99%

Role of Exosomes in the Regulation of T-Cell Mediated Immune Responses and in Autoimmune Disease

Anel

Gallego-Lleyda

Miguel

et al. 2019

Cells

130

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: T-cell mediated immune responses should be regulated to avoid the development of autoimmune or chronic inflammatory diseases. Several mechanisms have been described to regulate this process, namely death of overactivated T cells by cytokine deprivation, suppression by T regulatory cells (Treg), induction of expression of immune checkpoint molecules such as CTLA-4 and PD-1, or activation-induced cell death (AICD). In addition, activated T cells release membrane microvesicles called exosomes during these regulatory processes. In this review, we revise the role of exosome secretion in the different pathways of immune regulation described to date and its importance in the prevention or development of autoimmune disease. The expression of membrane-bound death ligands on the surface of exosomes during AICD or the more recently described transfer of miRNA or even DNA inside T-cell exosomes is a molecular mechanism that will be analyzed.

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“…It is now established that, independently of this function, p21 is a central regulator of innate and adaptive immunity (39)(40)(41)(42)(43). p21 suppresses autoimmunity through T cell regulation (44), and we recently described a therapeutic effect for p21 through regulation of memory T cell responses and IFN-γ production in lupus-prone mice (45).…”

Section: Introductionmentioning

confidence: 99%

p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β

Rackov¹,

Hernández-Jiménez²,

Shokri³

et al. 2016

Journal of Clinical Investigation

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M1 and M2 macrophage phenotypes, which mediate proinflammatory and antiinflammatory functions, respectively, represent the extremes of immunoregulatory plasticity in the macrophage population. This plasticity can also result in intermediate macrophage states that support a balance between these opposing functions. In sepsis, M1 macrophages can compensate for hyperinflammation by acquiring an M2-like immunosuppressed status that increases the risk of secondary infection and death. The M1 to M2 macrophage reprogramming that develops during LPS tolerance resembles the pathological antiinflammatory response to sepsis. Here, we determined that p21 regulates macrophage reprogramming by shifting the balance between active p65-p50 and inhibitory p50-p50 NF-κB pathways. p21 deficiency reduced the DNA-binding affinity of the p50-p50 homodimer in LPS-primed and -rechallenged macrophages, impairing their ability to attenuate IFN-β production and acquire an M2-like hyporesponsive status. High p21 levels in sepsis patients correlated with low IFN-β expression, and p21 knockdown in human monocytes corroborated its role in IFN-β regulation. The data demonstrate that p21 adjusts the equilibrium between p65-p50 and p50-p50 NF-κB pathways to mediate macrophage plasticity in LPS tolerance. Identifying p21-related pathways involved in monocyte reprogramming may lead to potential targets for sepsis treatment.

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Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production

Cited by 26 publications

References 55 publications

Adaptive immune responses are altered in adult mice following neonatal hyperoxia

Adaptive immune responses are altered in adult mice following neonatal hyperoxia

Role of Exosomes in the Regulation of T-Cell Mediated Immune Responses and in Autoimmune Disease

p21 mediates macrophage reprogramming through regulation of p50-p50 NF-κB and IFN-β

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