Publications by authors named "Claudio Procaccini"

55 Publications

Caloric Restriction Promotes Immunometabolic Reprogramming Leading to Protection from Tuberculosis.

Cell Metab 2021 Feb 8;33(2):300-318.e12. Epub 2021 Jan 8.

Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy. Electronic address:

There is a strong relationship between metabolic state and susceptibility to Mycobacterium tuberculosis (MTB) infection, with energy metabolism setting the basis for an exaggerated immuno-inflammatory response, which concurs with MTB pathogenesis. Herein, we show that controlled caloric restriction (CR), not leading to malnutrition, protects susceptible DBA/2 mice against pulmonary MTB infection by reducing bacterial load, lung immunopathology, and generation of foam cells, an MTB reservoir in lung granulomas. Mechanistically, CR induced a metabolic shift toward glycolysis, and decreased both fatty acid oxidation and mTOR activity associated with induction of autophagy in immune cells. An integrated multi-omics approach revealed a specific CR-induced metabolomic, transcriptomic, and proteomic signature leading to reduced lung damage and protective remodeling of lung interstitial tightness able to limit MTB spreading. Our data propose CR as a feasible immunometabolic manipulation to control MTB infection, and this approach offers an unexpected strategy to boost immunity against MTB.
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http://dx.doi.org/10.1016/j.cmet.2020.12.016DOI Listing
February 2021

CD4 T Cell Defects in a Mulibrey Patient With Specific Mutations.

Front Immunol 2020 18;11:1742. Epub 2020 Sep 18.

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale "G. Salvatore", Consiglio Nazionale delle Ricerche, Naples, Italy.

Mulibrey (muscle-liver-brain-eye) syndrome (MUL) is an autosomal recessive disorder caused by mutations in the () gene, encoding for TRIM37 a member of the TRIM E3 ubiquitin ligase protein family. MUL patients are characterized by growth retardation, dysmorphic features, and a wide range of abnormalities affecting different organs. However, T-cell abnormalities have not been observed in MUL subjects, to date. Here we described the immunological features of a MUL child carrying recently identified mutations, a 17q22 deletion of maternal origin combined with a variant of paternal origin. Here we found quantitative and functional defects in CD4 T cells from this MUL case. Low levels of TRIM37 protein were specifically detected in CD4 T cells of MUL patient and associated with their altered proliferation and cytokine production. Of note, both CD4 and CD8 T lymphocytes of MUL child displayed an effector memory phenotype compared with healthy children. This clinical case research highlighted the possible role of TRIM37 in the control of immune cell number and function, especially in CD4 T cells. Finally, this study may contribute to the novel mechanistic studies aim of identifying, in depth, the role of the TRIM37 protein in the immune system.
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http://dx.doi.org/10.3389/fimmu.2020.01742DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7530177PMC
April 2021

Where Mitochondria Meet Autoimmunity: The Treg Cell Link.

Cell Metab 2020 Oct;32(4):507-509

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Treg Cell Lab, Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy. Electronic address:

Although a crucial role for mitochondrial metabolism in controlling T regulatory (Treg) cell function has been recognized, its contribution during autoimmunity has not yet been fully elucidated. In this issue of Cell Metabolism, Alissafi and colleagues demonstrate that during autoimmunity, Treg cell functional alterations associate with mitochondrial oxidative stress, dysfunctional mitophagy, and enhanced DNA damage response, culminating with their cell death.
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http://dx.doi.org/10.1016/j.cmet.2020.08.006DOI Listing
October 2020

T1D progression is associated with loss of CD3CD56 regulatory T cells that control CD8 T cell effector functions.

Nat Metab 2020 02 17;2(2):142-152. Epub 2020 Feb 17.

Laboratorio di Immunologia, Istituto per l'Endocrinologia e l'Oncologia Sperimentale G. Salvatore, Consiglio Nazionale delle Ricerche, Naples, Italy.

An unresolved issue in autoimmunity is the lack of surrogate biomarkers of immunological self-tolerance for disease monitoring. Here, we show that peripheral frequency of a regulatory T cell population, characterized by the co-expression of CD3 and CD56 molecules (T), is reduced in subjects with new-onset type 1 diabetes (T1D). In three independent T1D cohorts, we find that low frequency of circulating T cells is associated with reduced β-cell function and with the presence of diabetic ketoacidosis. As autoreactive CD8 T cells mediate disruption of insulin-producing β-cells, we demonstrate that T cells can suppress CD8 T cell functions by reducing levels of intracellular reactive oxygen species. The suppressive function, phenotype and transcriptional signature of T cells are also altered in T1D children. Together, our findings indicate that T cells constitute a regulatory cell population that controls CD8 effector functions, whose peripheral frequency may represent a traceable biomarker for monitoring immunological self-tolerance in T1D.
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http://dx.doi.org/10.1038/s42255-020-0173-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7272221PMC
February 2020

PTX3: an inflammatory protein modulating ultrastructure and bioenergetics of human endothelial cells.

Immun Ageing 2019 2;16. Epub 2019 Feb 2.

1Vascular Pathophysiology Unit, IRCCS Neuromed, 86077 Pozzilli, IS Italy.

Background: Pentraxin 3 (PTX3), an acute-phase inflammation protein produced by several cell types, has long been described as a possible biomarker for age-related cardiovascular and cerebrovascular diseases. Although several mechanisms of action have been identified to date in the vascular and immune systems, the direct effects of PTX3 on isolated endothelial cells at morphological and metabolic levels remain unknown.

Findings: PTX3 induced cytoplasmic vacuolization and dilution of mitochondrial matrix in isolated, human endothelial cells. Moreover, metabolic assays revealed that PTX3 increases respiratory capacity in support of mitochondrial function, and partially sustains the glycolytic pathway.

Conclusions: PTX3 has, per se a direct action on ultrastructural and bioenergetic parameters of isolated endothelial cells. This finding can be associated with our previous demonstration of a deleterious effect of PTX3 on the endothelial layer. More studies are needed to clearly demonstrate any direct correlation between these ultrastructural and bioenergetic changes with endothelial dysfunction, especially with regard to age-related cerebro- and cardio-vascular diseases.
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http://dx.doi.org/10.1186/s12979-019-0144-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6359806PMC
February 2019

IFNβ enhances mesenchymal stromal (Stem) cells immunomodulatory function through STAT1-3 activation and mTOR-associated promotion of glucose metabolism.

Cell Death Dis 2019 01 28;10(2):85. Epub 2019 Jan 28.

IRCCS Ospedale Policlinico San Martino, Genoa, Italy.

Administration of mesenchymal stem cells (MSC) ameliorate experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis (MS), at both clinical and neuropathological levels. The therapeutic properties of MSC in EAE are mainly mediated by the modulation of pathogenic immune response, but other neurotropic effects, including decreased demyelination and axonal loss as well as promotion of tissue repair, play also a role. Properly controlled phase II clinical trials to explore the potential of MSC transplantation as a treatment for MS are underway. Interferon beta (IFNβ) is an approved treatment for relapsing-remitting and secondary progressive MS. Here, we explored the possibility that IFNβ might influence the therapeutic potential of MSC, in view of possible synergistic effects as add-on therapy. IFNβ enhanced the immunomodulatory functions of MSC and induced the expression of secretory leukocyte protease inhibitor (Slpi) and hepatocyte growth factor (Hgf), two soluble mediators involved in immune and regenerative functions of MSC. At molecular level, IFNβ induced a rapid and transient phosphorylation of STAT1 and STAT3, the transcription factors responsible for Slpi and Hgf induction. Concomitantly, IFNβ dynamically affected the activity of mTOR, a key checkpoint in the control of metabolic pathways. Indeed, the impairment of mTOR activity observed early upon exposure to IFNβ, was followed by a long-lasting induction of mTOR signaling, that was associated with an increased glycolytic capacity in MSC. When induced to switch their energetic metabolism towards glycolysis, MSC showed an improved ability to control T-cell proliferation. These results suggest that modifications of MSC energetic metabolism induced by IFNβ may contribute to promote MSC immunomodulatory function and support a role for metabolic pathways in the therapeutic function of MSC. Altogether, these findings support the idea of a combined treatment for MS, in which the immunomodulatory and possibly regenerative activity of MSC could be enhanced by the administration of IFNβ.
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http://dx.doi.org/10.1038/s41419-019-1336-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349843PMC
January 2019

Drp1 Controls Effective T Cell Immune-Surveillance by Regulating T Cell Migration, Proliferation, and cMyc-Dependent Metabolic Reprogramming.

Cell Rep 2018 12;25(11):3059-3073.e10

Department of Biology, University of Rome Tor Vergata, Rome, Italy; IRCCS, Fondazione Santa Lucia, Rome, Italy. Electronic address:

Mitochondria are key players in the regulation of T cell biology by dynamically responding to cell needs, but how these dynamics integrate in T cells is still poorly understood. We show here that the mitochondrial pro-fission protein Drp1 fosters migration and expansion of developing thymocytes both in vitro and in vivo. In addition, we find that Drp1 sustains in vitro clonal expansion and cMyc-dependent metabolic reprogramming upon activation, also regulating effector T cell numbers in vivo. Migration and extravasation defects are also exhibited in Drp1-deficient mature T cells, unveiling its crucial role in controlling both T cell recirculation in secondary lymphoid organs and accumulation at tumor sites. Moreover, the observed Drp1-dependent imbalance toward a memory-like phenotype favors T cell exhaustion in the tumor microenvironment. All of these findings support a crucial role for Drp1 in several processes during T cell development and in anti-tumor immune-surveillance.
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http://dx.doi.org/10.1016/j.celrep.2018.11.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6302735PMC
December 2018

AMBRA1 Controls Regulatory T-Cell Differentiation and Homeostasis Upstream of the FOXO3-FOXP3 Axis.

Dev Cell 2018 12;47(5):592-607.e6

IRCCS Fondazione Santa Lucia, Rome 00143, Italy.

Regulatory T cells (T) are necessary to maintain immunological tolerance and are key players in the control of autoimmune disease susceptibility. Expression of the transcription factor FOXP3 is essential for differentiation of T cells and indispensable for their suppressive function. However, there is still a lack of knowledge about the mechanisms underlying its regulation. Here, we demonstrate that pro-autophagy protein AMBRA1 is also a key modulator of T cells, regulating the complex network that leads to human T differentiation and maintenance. Indeed, through its ability to interact with the phosphatase PP2A, AMBRA1 promotes the stability of the transcriptional activator FOXO3, which, in turn, triggers FOXP3 transcription. Furthermore, we found that AMBRA1 plays a significant role in vivo by regulating T cell induction in mouse models of both tumor growth and multiple sclerosis, thus highlighting the role of AMBRA1 in the control of immune homeostasis.
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http://dx.doi.org/10.1016/j.devcel.2018.11.010DOI Listing
December 2018

Fatty acid metabolism complements glycolysis in the selective regulatory T cell expansion during tumor growth.

Proc Natl Acad Sci U S A 2018 07 25;115(28):E6546-E6555. Epub 2018 Jun 25.

Dipartimento di Medicina Interna e Specialità Mediche, Sapienza Università di Roma, 00161 Rome, Italy;

The tumor microenvironment restrains conventional T cell (Tconv) activation while facilitating the expansion of Tregs. Here we showed that Tregs' advantage in the tumor milieu relies on supplemental energetic routes involving lipid metabolism. In murine models, tumor-infiltrating Tregs displayed intracellular lipid accumulation, which was attributable to an increased rate of fatty acid (FA) synthesis. Since the relative advantage in glucose uptake may fuel FA synthesis in intratumoral Tregs, we demonstrated that both glycolytic and oxidative metabolism contribute to Tregs' expansion. We corroborated our data in human tumors showing that Tregs displayed a gene signature oriented toward glycolysis and lipid synthesis. Our data support a model in which signals from the tumor microenvironment induce a circuitry of glycolysis, FA synthesis, and oxidation that confers a preferential proliferative advantage to Tregs, whose targeting might represent a strategy for cancer treatment.
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http://dx.doi.org/10.1073/pnas.1720113115DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6048537PMC
July 2018

GRK2 moderates the acute mitochondrial damage to ionizing radiation exposure by promoting mitochondrial fission/fusion.

Cell Death Discov 2018 Dec 14;4:25. Epub 2018 Feb 14.

3Department of Medicine, Surgery and Dentistry, University of Salerno, Baronissi, Italy.

The modern understanding of the G protein-coupled receptor kinase 2 has grown towards the definition of a stress protein, for its ability to rapidly compartmentalize within the cell in response to acute stimulation. Also, mitochondria can be regulated by GRK2 localization. We show that Ionizing Radiation (IR) exposure acutely damages mitochondria regarding mass, morphology, and respiration, with recovery in a framework of hours. This phenomenon is actively regulated by GRK2, whose overexpression results to be protective, and reciprocally, deletion accelerates degenerative processes. The regulatory effects of the kinase involve a new interactome that includes binding HSP90 and binding and phosphorylation of the key molecules involved in the process of mitochondrial fusion and recovery: MFN-1 and 2.
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http://dx.doi.org/10.1038/s41420-018-0028-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5841414PMC
December 2018

Prep1 deficiency improves metabolic response in white adipose tissue.

Biochim Biophys Acta Mol Cell Biol Lipids 2018 May 21;1863(5):515-525. Epub 2018 Feb 21.

Department of Translational Medicine, Federico II University of Naples and URT "Genomic of Diabetes" of Institute of Experimental Endocrinology and Oncology, National Council of Research (CNR), Naples, Italy. Electronic address:

Prep1 is a gene encoding for a homeodomain transcription factor which induces hepatic and muscular insulin resistance. In this study, we show that Prep1 hypomorphic heterozygous (Prep1) mice, expressing low levels of protein, featured a 23% and a 25% reduction of total body lipid content and epididymal fat, respectively. The percentage of the small adipocytes (25-75 μm) was 30% higher in Prep1 animals than in the WT, with a reciprocal difference in the large adipose cells (100-150 and >150 μm). Insulin-stimulated insulin receptor tyrosine and Akt serine phosphorylation markedly increased in Prep1 mice, paralleled by 3-fold higher glucose uptake and a significant increase of proadipogenic genes such as C/EBPα, GLUT4, and FABP4. Moreover, T cells infiltration and TNF-α, IFNγ and leptin expression were reduced in adipose tissue from Prep1 mice, while adiponectin levels were 2-fold higher. Furthermore, Prep1 mature adipocytes released lower amounts of pro-inflammatory cytokines and higher amount of adiponectin compared to WT cells. Incubation of murine liver cell line (NMuLi) with conditioned media (CM) from mature adipocytes of Prep1 mice improved glucose metabolism, while those from WT mice had no effect. Consistent with these data, Prep1 overexpression in 3T3-L1 adipocytes impaired adipogenesis and insulin signaling, and increased proinflammatory cytokine secretion. All these findings suggest that Prep1 silencing reduces inflammatory response and increases insulin sensitivity in adipose tissue. In addition, CM from mature adipocytes of Prep1 mice improve metabolism in hepatic cells.
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http://dx.doi.org/10.1016/j.bbalip.2018.02.005DOI Listing
May 2018

Altered Bioenergetic Profile in Umbilical Cord and Amniotic Mesenchymal Stem Cells from Newborns of Obese Women.

Stem Cells Dev 2018 02 3;27(3):199-206. Epub 2018 Jan 3.

1 CEINGE Biotecnologie Avanzate S.C.a R.L. , Naples, Italy .

Nutritional imbalance and metabolic alterations associated with maternal obesity during pregnancy predispose offspring to obesity and/or to type 2 diabetes, but the mechanisms underlying these effects are still obscure. In this context, we evaluated whether the two main energy-producing pathways (glycolysis and mitochondrial oxidative phosphorylation) are impaired in obesity during pregnancy thus contributing to metabolic intrauterine alterations. Specifically, we studied metabolic abnormalities in the intrauterine life of newborns using stem cells isolated from amnion and umbilical cord (hA- and hUC-MSCs). We isolated, at delivery, neonatal hUC-MSCs from 13 obese (Ob) and 10 normal weight control (Co) women (prepregnancy body mass index >30 and <25 kg/m, respectively) and hA-MSCs from a subgroup of 3 Ob and 3 Co women. The hUC-MSC immunophenotype was characterized by flow cytometry. The extracellular acidification rate and oxygen consumption rate, which are indicators of glycolysis and mitochondrial respiration, respectively, were measured using the Seahorse XFe96 analyzer. Basal glycolysis (Co: 27.5 ± 2.9; Ob: 21.3 ± 2.3 mpH/min) and glycolytic capacity (Co: 65.3 ± 1.2; Ob: 55.0 ± 0.3 mpH/min) were significantly lower in Ob-hUC-MSCs versus Co-hUC-MSCs (P < 0.05 and P < 0.0001, respectively). Mitochondrial basal respiration (Co: 46.9 ± 0.7; Ob: 32.6 ± 0.8 pmol/min), ATP-linked respiration (Co: 29.3 ± 1.9; Ob: 20.1 ± 0.3 pmol/min), and maximal respiration (Co: 75.2 ± 5.3; Ob: 50.5 ± 4.1 pmol/min) were significantly (P < 0.0001) lower in Ob-hUC-MSCs versus Co-hUC-MSCs. Similarly, bioenergetic profiles of the subgroup of Ob-hA-MSCs differed from those of Co-hA-MSCs. These results demonstrate that the bioenergetic performance of Ob-h-MSCs is lower in basal conditions and in conditions of increased energy demand compared with Co-h-MSCs. In conclusion, we describe a new mechanism whereby obesity alters intrauterine metabolism. This process could concur to predispose offspring to metabolic diseases in adult life.
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http://dx.doi.org/10.1089/scd.2017.0198DOI Listing
February 2018

Mitochondrial AKAP1 supports mTOR pathway and tumor growth.

Cell Death Dis 2017 06 1;8(6):e2842. Epub 2017 Jun 1.

Department of Molecular Medicine and Medical Biotechnologies, IEOS-CNR, University Federico II, Naples, Italy.

Mitochondria are the powerhouses of energy production and the sites where metabolic pathway and survival signals integrate and focus, promoting adaptive responses to hormone stimulation and nutrient availability. Increasing evidence suggests that mitochondrial bioenergetics, metabolism and signaling are linked to tumorigenesis. AKAP1 scaffolding protein integrates cAMP and src signaling on mitochondria, regulating organelle biogenesis, oxidative metabolism and cell survival. Here, we provide evidence that AKAP1 is a transcriptional target of Myc and supports the growth of cancer cells. We identify Sestrin2, a leucine sensor and inhibitor of the mammalian target of rapamycin (mTOR), as a novel component of the complex assembled by AKAP1 on mitochondria. Downregulation of AKAP1 impaired mTOR pathway and inhibited glioblastoma growth. Both effects were reversed by concomitant depletion of AKAP1 and sestrin2. High levels of AKAP1 were found in a wide variety of high-grade cancer tissues. In lung cancer, AKAP1 expression correlates with high levels of Myc, mTOR phosphorylation and reduced patient survival. Collectively, these data disclose a previously unrecognized role of AKAP1 in mTOR pathway regulation and cancer growth. AKAP1/mTOR signal integration on mitochondria may provide a new target for cancer therapy.
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http://dx.doi.org/10.1038/cddis.2017.241DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5520900PMC
June 2017

Metformin restores the mitochondrial network and reverses mitochondrial dysfunction in Down syndrome cells.

Hum Mol Genet 2017 03;26(6):1056-1069

Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, 80131 Naples, Italy.

Alterations in mitochondrial activity and morphology have been demonstrated in human cells and tissues from individuals with Down syndrome (DS), as well as in DS mouse models. An impaired activity of the transcriptional coactivator PGC-1α/PPARGC1A due to the overexpression of chromosome 21 genes, such as NRIP1/RIP140, has emerged as an underlying cause of mitochondrial dysfunction in DS. We tested the hypothesis that the activation of the PGC-1α pathway might indeed reverse this mitochondrial dysfunction. To this end, we investigated the effects of metformin, a PGC-1α-activating drug, on mitochondrial morphology and function in DS foetal fibroblasts. Metformin induced both the expression of PGC-1α and an augmentation of its activity, as demonstrated by the increased expression of target genes, strongly promoting mitochondrial biogenesis. Furthermore, metformin enhanced oxygen consumption, ATP production, and overall mitochondrial activity. Most interestingly, this treatment reversed the fragmentation of mitochondria observed in DS and induced the formation of a mitochondrial network with a branched and elongated tubular morphology. Concomitantly, cristae remodelling occurred and the alterations observed by electron microscopy were significantly reduced. We finally demonstrated that the expression of genes of the fission/fusion machinery, namely OPA1 and MFN2, was reduced in trisomic cells and increased by metformin treatment. These results indicate that metformin promotes the formation of a mitochondrial network and corrects the mitochondrial dysfunction in DS cells. We speculate that alterations in the mitochondrial dynamics can be relevant in the pathogenesis of DS and that metformin can efficiently counteract these alterations, thus exerting protective effects against DS-associated pathologies.
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http://dx.doi.org/10.1093/hmg/ddx016DOI Listing
March 2017

Metabolic control of immune tolerance in health and autoimmunity.

Semin Immunol 2016 10 5;28(5):491-504. Epub 2016 Oct 5.

Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), Napoli 80131, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli "Federico II", Napoli 80131, Italy. Electronic address:

The filed that links immunity and metabolism is rapidly expanding. The adipose tissue, by secreting a series of immune regulators called adipokines, represents the common mediator linking metabolic processes and immune system functions. The dysregulation of adipokine secretion, occurring in obese individuals or in conditions of malnutrition or dietary restriction, affects the activity of immune cells resulting in inflammatory autoimmune responses or increased susceptibility to infectious diseases. Alterations of cell metabolism that characterize several autoimmune diseases strongly support the idea that the immune tolerance is also regulated by metabolic pathways. The comprehension of the molecular mechanisms underlying these alterations may lead to the development of novel therapeutic strategies to control immune cell differentiation and function in conditions of autoimmunity.
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http://dx.doi.org/10.1016/j.smim.2016.09.006DOI Listing
October 2016

IFN-γ orchestrates mesenchymal stem cell plasticity through the signal transducer and activator of transcription 1 and 3 and mammalian target of rapamycin pathways.

J Allergy Clin Immunol 2017 May 23;139(5):1667-1676. Epub 2016 Sep 23.

Dipartimento di Neuroscienze, Riabilitazione, Oftalmologia, Genetica e Scienze Materno-infantili, Facoltà di Medicina e Chirurgia, Università di Genova, Genoa, Italy; Center of Excellence for Biomedical Research (CEBR), Genoa, Italy; IRCCS AOU San Martino-IST, Genoa, Italy. Electronic address:

Background: Mesenchymal stem cells (MSCs) display a therapeutic plasticity because of their ability to modulate immunity, foster tissue repair, and differentiate into mesodermal cells. IFN-γ has been described to differently affect human mesenchymal stem cell (hMSC) and mouse mesenchymal stem cell (mMSC) immunomodulation and differentiation, depending on the inflammatory milieu.

Objective: We aimed at dissecting the relevant intracellular pathways through which IFN-γ affects MSC plasticity and the consequence of their manipulation on MSC functions.

Methods: Modification of relevant IFN-γ-dependent pathways in mMSCs was carried out in vitro through gene silencing or chemical inhibition of key components. Functional outcomes were assessed by means of Western blotting, real-time PCR, differentiation, and proliferation assays on MSCs. The effect on T cells was addressed by T-cell proliferation assays; the effect of mammalian target of rapamycin (mTOR) manipulation in MSCs was studied in vivo in a mouse model of delayed-type hypersensitivity assay. To address whether similar mechanisms are involved also in hMSCs on IFN-γ stimulation, the effect of chemical inhibition on the same intracellular pathways was assessed by means of Western blotting, and the final outcome on immunomodulatory properties was evaluated based on real-time PCR and T-cell proliferation.

Results: We revealed that in mMSCs IFN-γ-induced immunoregulation is mediated by early phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3, which is significantly enhanced by an extracellular signal-regulated kinase 1/2-dependent mTOR inhibition, thereby promoting pSTAT1 nuclear translocation. Accordingly, after intracellular mTOR inhibition, MSCs augmented their ability to inhibit T-cell proliferation and control delayed-type hypersensitivity in vivo. Similarly, on mTOR blockade, hMSCs also enhanced their immunoregulatory features. A sustained exposure to IFN-γ led to inhibition of STAT3 activity, which in mMSCs resulted in an impaired proliferation and differentiation.

Conclusion: These results provide new insights about MSC intracellular pathways affected by IFN-γ, demonstrating that pharmacologic or genetic manipulation of MSCs can enhance their immunomodulatory functions, which could be translated into novel therapeutic approaches.
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http://dx.doi.org/10.1016/j.jaci.2016.09.004DOI Listing
May 2017

Convergent Effects of Resveratrol and PYK2 on Prostate Cells.

Int J Mol Sci 2016 Sep 13;17(9). Epub 2016 Sep 13.

Department of Molecular Medicine and Medical Biotechnologies, University of Naples "Federico II", 80131 Naples, Italy.

Resveratrol, a dietary polyphenol, is under consideration as chemopreventive and chemotherapeutic agent for several diseases, including cancer. However, its mechanisms of action and its effects on non-tumor cells, fundamental to understand its real efficacy as chemopreventive agent, remain largely unknown. Proline-rich tyrosine kinase 2 (PYK2), a non-receptor tyrosine kinase acting as signaling mediator of different stimuli, behaves as tumor-suppressor in prostate. Since, PYK2 and RSV share several fields of interaction, including oxidative stress, we have investigated their functional relationship in human non-transformed prostate EPN cells and in their tumor-prone counterpart EPN-PKM, expressing a PYK2 dead-kinase mutant. We show that RSV has a strong biological activity in both cell lines, decreasing ROS production, inducing morphological changes and reversible growth arrest, and activating autophagy but not apoptosis. Interestingly, the PYK2 mutant increases basal ROS and autophagy levels, and modulates the intensity of RSV effects. In particular, the anti-oxidant effect of RSV is more potent in EPN than in EPN-PKM, whereas its anti-proliferative and pro-autophagic effects are more significant in EPN-PKM. Consistently, PYK2 depletion by RNAi replicates the effects of the PKM mutant. Taken together, our results reveal that PYK2 and RSV act on common cellular pathways and suggest that RSV effects on prostate cells may depend on mutational-state or expression levels of PYK2 that emerges as a possible mediator of RSV mechanisms of action. Moreover, the observation that resveratrol effects are reversible and not associated to apoptosis in tumor-prone EPN-PKM cells suggests caution for its use in humans.
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http://dx.doi.org/10.3390/ijms17091542DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5037816PMC
September 2016

Role of metabolism in neurodegenerative disorders.

Metabolism 2016 09 7;65(9):1376-90. Epub 2016 Jun 7.

Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131, Napoli, Italy. Electronic address:

Along with the increase in life expectancy over the last century, the prevalence of age-related disorders, such as neurodegenerative diseases continues to rise. This is the case of Alzheimer's, Parkinson's, Huntington's diseases and Multiple sclerosis, which are chronic disorders characterized by neuronal loss in motor, sensory or cognitive systems. Accumulating evidence has suggested the presence of a strong correlation between metabolic changes and neurodegeneration. Indeed epidemiologic studies have shown strong associations between obesity, metabolic dysfunction, and neurodegeneration, while animal models have provided insights into the complex relationships between these conditions. In this context, hormones such as leptin, ghrelin, insulin and IGF-1 seem to play a key role in the regulation of neuronal damage, toxic insults and several other neurodegenerative processes. This review aims to presenting the most recent evidence supporting the crosstalk linking energy metabolism and neurodegeneration, and will focus on metabolic manipulation as a possible therapeutic tool in the prevention and treatment of neurodegenerative diseases.
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http://dx.doi.org/10.1016/j.metabol.2016.05.018DOI Listing
September 2016

Leptin as immune mediator: Interaction between neuroendocrine and immune system.

Dev Comp Immunol 2017 01 8;66:120-129. Epub 2016 Jun 8.

Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), c/o Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II", 80131 Napoli, Italy. Electronic address:

Leptin is an adipocyte-derived hormone/cytokine that links nutritional status with neuroendocrine and immune functions. Initially described as an anti-obesity hormone, leptin has subsequently been shown to exert pleiotropic effects, being also able to influence haematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect both innate and adaptive immunity, by inducing a pro-inflammatory response and thus playing a key role in the regulation of the pathogenesis of several autoimmune/inflammatory diseases. In this review, we discuss the most recent advances on the role of leptin as immune-modulator in mammals and we also provide an overview on its main functions in non-mammalian vertebrates.
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http://dx.doi.org/10.1016/j.dci.2016.06.006DOI Listing
January 2017

The Proteomic Landscape of Human Ex Vivo Regulatory and Conventional T Cells Reveals Specific Metabolic Requirements.

Immunity 2016 Feb;44(2):406-21

Laboratorio di Immunologia, Istituto di Endocrinologia e Oncologia Sperimentale, Consiglio Nazionale delle Ricerche (IEOS-CNR), 80131 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli "Federico II," 80131 Napoli, Italy. Electronic address:

Human CD4(+)CD25(hi)Foxp3(+)CD127(-) Treg and CD4(+)CD25(-)Foxp3(-) Tconv cell functions are governed by their metabolic requirements. Here we report a comprehensive comparative analysis between ex vivo human Treg and Tconv cells that comprises analyses of the proteomic networks in subcellular compartments. We identified a dominant proteomic signature at the metabolic level that primarily impacted the highly-tuned balance between glucose and fatty-acid oxidation in the two cell types. Ex vivo Treg cells were highly glycolytic while Tconv cells used predominantly fatty-acid oxidation (FAO). When cultured in vitro, Treg cells engaged both glycolysis and FAO to proliferate, while Tconv cell proliferation mainly relied on glucose metabolism. Our unbiased proteomic analysis provides a molecular picture of the impact of metabolism on ex vivo human Treg versus Tconv cell functions that might be relevant for therapeutic manipulations of these cells.
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http://dx.doi.org/10.1016/j.immuni.2016.01.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4760097PMC
February 2016

Glycolysis controls the induction of human regulatory T cells by modulating the expression of FOXP3 exon 2 splicing variants.

Nat Immunol 2015 Nov 28;16(11):1174-84. Epub 2015 Sep 28.

Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy.

Human regulatory T cells (T(reg) cells) that develop from conventional T cells (T(conv) cells) following suboptimal stimulation via the T cell antigen receptor (TCR) (induced T(reg) cells (iT(reg) cells)) express the transcription factor Foxp3, are suppressive, and display an active proliferative and metabolic state. Here we found that the induction and suppressive function of iT(reg) cells tightly depended on glycolysis, which controlled Foxp3 splicing variants containing exon 2 (Foxp3-E2) through the glycolytic enzyme enolase-1. The Foxp3-E2-related suppressive activity of iT(reg) cells was altered in human autoimmune diseases, including multiple sclerosis and type 1 diabetes, and was associated with impaired glycolysis and signaling via interleukin 2. This link between glycolysis and Foxp3-E2 variants via enolase-1 shows a previously unknown mechanism for controlling the induction and function of T(reg) cells in health and in autoimmunity.
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http://dx.doi.org/10.1038/ni.3269DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4868085PMC
November 2015

Polychlorinated Biphenyls Induce Mitochondrial Dysfunction in SH-SY5Y Neuroblastoma Cells.

PLoS One 2015 23;10(6):e0129481. Epub 2015 Jun 23.

Dept. of Science and Technology-DST, University of Sannio, via Port'Arsa 11, 82100 Benevento, Italy.

Chronic exposure to polychlorinated biphenyls (PCBs), ubiquitous environmental contaminants, can adversely affect the development and function of the nervous system. Here we evaluated the effect of PCB exposure on mitochondrial function using the PCB mixture Aroclor-1254 (A1254) in SH-SY5Y neuroblastoma cells. A 6-hour exposure to A1254 (5 μg/ml) reduced cellular ATP production by 45%±7, and mitochondrial membrane potential, detected by TMRE, by 49%±7. Consistently, A1254 significantly decreased oxidative phosphorylation and aerobic glycolysis measured by extracellular flux analyzer. Furthermore, the activity of mitochondrial protein complexes I, II, and IV, but not V (ATPase), measured by BN-PAGE technique, was significantly reduced after 6-hour exposure to A1254. The addition of pyruvic acid during exposure to A1254 significantly prevent A1254-induced cell injury, restoring resting mitochondrial membrane potential, ATP levels, oxidative phosphorylation and aerobic glycolysis. Furthermore, pyruvic acid significantly preserved the activity of mitochondrial complexes I, II and IV and increased basal activity of complex V. Collectively, the present results indicate that the neurotoxicity of A1254 depends on the impairment of oxidative phosphorylation, aerobic glycolysis, and mitochondrial complexes I, II, and IV activity and it was counteracted by pyruvic acid.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0129481PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4477897PMC
April 2016

Animal models of Multiple Sclerosis.

Eur J Pharmacol 2015 Jul 27;759:182-91. Epub 2015 Mar 27.

Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno, Baronissi Campus, 84081 Baronissi, Salerno, Italy; IRCCS Multimedica, 20138 Milano, Italy. Electronic address:

Multiple Sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) which involves a complex interaction between immune system and neural cells. Animal modeling has been critical for addressing MS pathogenesis. The three most characterized animal models of MS are (1) the experimental autoimmune/allergic encephalomyelitis (EAE); (2) the virally-induced chronic demyelinating disease, known as Theiler׳s murine encephalomyelitis virus (TMEV) infection and (3) the toxin-induced demyelination. All these models, in a complementary way, have allowed to reach a good knowledge of the pathogenesis of MS. Specifically, EAE is the model which better reflects the autoimmune pathogenesis of MS and is extremely useful to study potential experimental treatments. Furthermore, both TMEV and toxin-induced demyelination models are suitable for characterizing the role of the axonal injury/repair and the remyelination process in MS. In conclusion, animal models, despite their limitations, remain the most useful instrument for implementing the study of MS.
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http://dx.doi.org/10.1016/j.ejphar.2015.03.042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7094661PMC
July 2015

Pentraxin 3 Induces Vascular Endothelial Dysfunction Through a P-selectin/Matrix Metalloproteinase-1 Pathway.

Circulation 2015 Apr 6;131(17):1495-505; discussion 1505. Epub 2015 Mar 6.

From IRCCS Neuromed, Pozzilli, Italy (A.C., A.D., F.B., M.A., M.M., F.F., C.V.); University of Pisa, Department of Human Morphology and Applied Biology, Italy (P.L., F.F.); Laboratory of Immunology, Institute of Experimental Endocrinology and Oncology, National Research Council of Italy (IEOS-CNR), c/o Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Napoli, Italy; (C.P., V.G.); University of Salerno, Department of Pharmaceutical Sciences, Fisciano (Salerno), Italy (G.A.); University of Salerno, Medicine and Surgery, Baronissi (Salerno), Italy (G.A., P.R., A.A.P., G.M., C.V.); Hypertension Research Center and Department of Advanced Biomedical Sciences (D.G.C., B.T.) and Department of Translational Medical Sciences (R.I.), University of Naples "Federico II", Napoli, Italy; University of Pavia, Department of Industrial and Information Engineering, Italy (A. Malovini); Department of Science and Technology, University of Sannio, Benevento, Italy (L.F.); Pathology Unit, "Istituto Nazionale Tumori, IRCCS, Fondazione Pascale," Naples, Italy (V.G.); and IRCCS Multimedica, Milan, Italy (A.A.P., G.M.).

Background: Pentraxin 3 (PTX3), the prototype of long pentraxins, has been described to be associated with endothelial dysfunction in different cardiovascular disorders. No study has yet evaluated the possible direct effect of PTX3 on vascular function.

Methods And Results: Through in vitro experiments of vascular reactivity and ultrastructural analyses, we demonstrate that PTX3 induces dysfunction and morphological changes in the endothelial layer through a P-selectin/matrix metalloproteinase-1 pathway. The latter hampered the detachment of endothelial nitric oxide synthase from caveolin-1, leading to an impairment of nitric oxide signaling. In vivo studies showed that administering PTX3 to wild-type mice induced endothelial dysfunction and increased blood pressure, an effect absent in P-selectin-deficient mice. In isolated human umbilical vein endothelial cells, PTX3 significantly blunted nitric oxide production through the matrix metalloproteinase-1 pathway. Finally, using ELISA, we found that hypertensive patients (n=31) have higher plasma levels of PTX3 and its mediators P-selectin and matrix metalloproteinase-1 than normotensive subjects (n=21).

Conclusions: Our data show for the first time a direct role of PTX3 on vascular function and blood pressure homeostasis, identifying the molecular mechanisms involved. The findings in humans suggest that PTX3, P-selectin, and matrix metalloproteinase-1 may be novel biomarkers that predict the onset of vascular dysfunction in hypertensive patients.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.114.014822DOI Listing
April 2015

Immune-metabolic profiling of anorexic patients reveals an anti-oxidant and anti-inflammatory phenotype.

Metabolism 2015 Mar 29;64(3):396-405. Epub 2014 Oct 29.

CEINGE-Biotecnologie Avanzate S.C.a R.L., via G. Salvatore 482, 80145 Napoli, Italy; Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università di Napoli Federico II, via S. Pansini 5, 80131 Napoli, Italy. Electronic address:

Context: Anorexia nervosa (AN) is an excessive form of calorie restriction (CR) associated with pathological weight loss and alterations of the immune system. However, AN patients seem to be protected from common viral infections.

Objectives: To investigate the metabolic and molecular adaptations induced by sustained extreme CR in the peripheral blood mononuclear cells (PBMCs) of patients with restrictive alimentary AN.

Design: Inflammatory cytokines and adipokines were measured in 15 young (age range, 15-24 years) AN female patients and 20 age-matched healthy controls. Isolated PBMCs were immunophenotyped by flow cytometry, and glycolysis and mitochondrial respiration were determined by measuring the extracellular acidification and oxygen consumption rate. Stress resistance to H2O2 and the antioxidant transcriptional profile of PBMCs and human fibroblasts incubated with sera from AN patients were also determined.

Results: Compared with controls, AN patients (BMI, 15.9±0.4 kg/m(2)) had significantly fewer leucocytes, lymphocytes and NK cells, lower serum concentrations of leptin, IGF-1 and sTNFR1, and higher levels of adiponectin, sCD40L and sICAM-1 (p<0.05). IL-1β, TNFα, and IL-6 produced by PBMC cultured with autologous serum for 48 h were significantly lower in AN patients than in controls (p<0.01). Moreover, glycolysis and mitochondrial respiration were lower, and the antioxidant transcriptional profile was higher in the PBMCs of AN patients. Fibroblasts cultured in serum from AN patients showed a 24% increase in resistance to H2O2 damage.

Conclusions: Extreme CR in AN patients is associated with a reduction in several immune cell populations, but with higher antioxidant potential, stress resistance and an anti-inflammatory status.
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http://dx.doi.org/10.1016/j.metabol.2014.10.025DOI Listing
March 2015

Leptin in autoimmune diseases.

Metabolism 2015 Jan 23;64(1):92-104. Epub 2014 Oct 23.

Dipartimento di Medicina e Chirurgia, Facoltà di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, 84081 Baronissi, Salerno, Italy; IRCCS-MultiMedica, 20138 Milano, Italy. Electronic address:

The past twenty years of research on leptin has provided crucial information on the link between metabolic state and immune system function. Adipocytes influence not only the endocrine system but also the immune response, through several cytokine-like mediators known as adipokines, which include leptin. Initially described as an antiobesity hormone, leptin has subsequently been shown also to influence hematopoiesis, thermogenesis, reproduction, angiogenesis, and more importantly immune homeostasis. As a cytokine, leptin can affect thymic homeostasis and the secretion of acute-phase reactants such as interleukin-1 (IL-1) and tumor-necrosis factor-alpha (TNF-α). Leptin links nutritional status and proinflammatory T helper 1 (Th1) immune responses and the decrease in leptin plasma concentration during food deprivation leads to impaired immune function. Conversely, elevated circulating leptin levels in obesity appear to contribute to the low-grade inflammatory background which makes obese individuals more susceptible to increased risk of developing cardiovascular diseases, diabetes, or degenerative disease including autoimmunity and cancer. In this review, we provide an overview of recent advances on the role of leptin in the pathogenesis of several autoimmune disorders that may be of particular relevance in the modulation of the autoimmune attack through metabolic-based therapeutic approaches.
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http://dx.doi.org/10.1016/j.metabol.2014.10.014DOI Listing
January 2015

Leptin modulates autophagy in human CD4+CD25- conventional T cells.

Metabolism 2014 Oct 19;63(10):1272-9. Epub 2014 Jun 19.

Dipartimento di Medicina e Chirurgia, Facoltà di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, 84081 Baronissi, Salerno, Italy; IRCCS-MultiMedica, 20138 Milano, Italy. Electronic address:

Objective: In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4(+)CD25(-) conventional (Tconv) T cells.

Results: In vitro treatment with recombinant human leptin determined an inhibition of autophagy during T cell receptor (TCR) stimulation, and this phenomenon was dose- and time-dependent. The events were secondary to the activation of the mammalian-target of rapamycin (mTOR)-pathway induced by leptin, as testified by its reversion induced by mTOR inhibition with rapamycin. At molecular level these phenomena associated with Bcl-2 up-regulation and its interaction with Beclin-1, whose complex exerts a negative effect on autophagy.

Materials/methods: The impact of leptin on autophagy of Tconv cells was determined at biochemical level by western blotting and by flow cytometry; the interaction between BCL-2 and Beclin-1 by co-immunoprecipitation assays.

Conclusions: Our results, suggest that in unconditioned, freshly-isolated human Tconv cells, autophagy and proliferation are controlled by leptin during TCR-engagement, and that both phenomena occur alternatively indicating a balance between these processes during immune activation.
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http://dx.doi.org/10.1016/j.metabol.2014.06.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4180014PMC
October 2014

Neuro-endocrine networks controlling immune system in health and disease.

Front Immunol 2014 7;5:143. Epub 2014 Apr 7.

Dipartimento di Medicina e Chirurgia, Università degli Studi di Salerno , Salerno , Italy ; IRCCS Multimedica , Milano , Italy.

The nervous and immune systems have long been considered as compartments that perform separate and different functions. However, recent clinical, epidemiological, and experimental data have suggested that the pathogenesis of several immune-mediated disorders, such as multiple sclerosis (MS), might involve factors, hormones, and neural mediators that link the immune and nervous system. These molecules are members of the same superfamily, which allow the mutual and bi-directional neural-immune interaction. More recently, the discovery of leptin, one of the most abundant adipocyte-derived hormones that control food intake and metabolism, has suggested that nutritional/metabolic status, acting at central level, can control immune self-tolerance, since it promotes experimental autoimmune encephalomyelitis, an animal model of MS. Here, we summarize the most recent advances and the key players linking the central nervous system, immune tolerance, and the metabolic status. Understanding this coordinated interaction may pave the way for novel therapeutic approaches to increase host defense and suppress immune-mediated disorders.
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http://dx.doi.org/10.3389/fimmu.2014.00143DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3985001PMC
June 2014

Regulatory T cell proliferative potential is impaired in human autoimmune disease.

Nat Med 2014 Jan 8;20(1):69-74. Epub 2013 Dec 8.

1] Dipartimento di Medicina e Chirurgia, Università di Salerno, Baronissi Campus, Baronissi, Salerno, Italy. [2] IRCCS MultiMedica, Milano, Italy.

Human CD4(+)CD25(high)CD127(-)FoxP3(+) regulatory T (Treg) cells suppress immune responses in vitro and in vivo. Reduced suppressive function and/or number of peripheral Treg cells has been previously reported in autoimmune disorders. Treg cells represent the most actively replicating compartment within the CD4(+) cells in vivo, but they are hyporesponsive to classical T cell receptor (TCR) stimulation in vitro, a condition that is secondary to their overactive metabolic state. Here we report that proliferation of Treg cells after TCR stimulation is impaired in subjects with relapsing-remitting multiple sclerosis (RRMS) because of altered interleukin-2 (IL-2) secretion and IL-2 receptor (IL-2R)-signal transducer and activator of transcription 5 (STAT5) signaling. This is associated with decreased expression of the forkhead box P3 (FoxP3) 44- and 47-kDa splicing forms, overactivation of S6 ribosomal protein (a downstream target of the mammalian target of rapamycin, mTOR) and altered activity of the cyclin-dependent kinase inhibitor p27 (p27(kip1)) and extracellular signal-related kinases 1 and 2 (ERK1/2). The impaired capacity of Treg cells to proliferate in RRMS correlates with the clinical state of the subject, where increasing disease severity is associated with a decline in Treg cell expansion. These results suggest a previously unrecognized mechanism that may account for the progressive loss of Treg cells in autoimmune disease.
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http://dx.doi.org/10.1038/nm.3411DOI Listing
January 2014