Martina Kunkl

Dottoressa di ricerca

ciclo: XXXII



Titolo della tesi: Role of CD28 in the regulation of IL-17A expression and in the modulation of the metabolic programs regulating pro-inflammatory T cell functions in Multiple Sclerosis

The immunopathogenesis of Multiple Sclerosis (MS) depends on the expansion of specific inflammatory T cell subsets, which are key effectors of tissue damage and demyelination. Several studies have evidenced that Th17 cells and IL-17-producing cells strongly contribute in initiating the autoimmune responses against components of the central nervous system. Therefore, the characterization of the mechanisms and molecules regulating IL-17 production and IL-17 producing cell amplification and functions could represent an important goal of the ongoing research in MS. CD28 is an important costimulatory receptor for T lymphocytes that, in humans, may deliver TCR-independent signal leading to the up-regulation of IL-17A expression in peripheral CD4+ T lymphocytes from MS patients. In this work, we characterized the mechanisms and signalling mediators responsible for CD28-induced IL-17A expression. We found that CD28-mediated up-regulation of IL- 17A was dependent on IL-6- associated STAT3 and RelA/NF-kB transcription factors, which following CD28 stimulation bind specific sequences on the IL-17A promoter, thus inducing its expression. Emerging studies also evidenced that a reprogramming of T cell metabolism regulates specific pro-inflammatory T cell responses and amplifies Th17 cells in MS. Starting from these evidences, we also characterized the involvement of CD28 and associated signalling mediators in the modulation of the metabolic programs regulating pro- inflammatory T cell functions in MS. Our data evidenced that CD28 stimulation up-regulates glycolysis by promoting the increase of c-myc and the glucose transporter, Glut1, in CD4+ T cells from relapsing- remitting (RR) MS patients. CD28-induced increase of glycolysis was required for the up-regulation of pro-inflammatory cytokines, as demonstrated by the strong inhibition exerted by a glycolysis inhibitor. By using specific inhibitory drugs, we also identified phosphatidylinositol 3 kinase (PI3K) as the critical regulator of CD28 proinflammatory and metabolic functions. These data suggest that CD28 may provide TCR- independent signals modulating the metabolic processes associated to specific pro-inflammatory T cell responses in MS.

Produzione scientifica

  • 11573/1086397 - 2018 - A non-conserved amino acid variant regulates differential signalling between human and mouse CD28 (01a Articolo in rivista)
    PORCIELLO, NICLA; GRAZIOLI, PAOLA; CAMPESE, ANTONIO FRANCESCO; KUNKL, MARTINA; CARISTI, SILVANA; MASTROGIOVANNI, MARTA; MUSCOLINI, MICHELA; SCREPANTI, ISABELLA; TUOSTO, LORETTA
  • 11573/963512 - 2017 - ISA-2011B, a phosphatidylinositol 4-phosphate 5-kinase a inhibitor, impairs CD28-dependent costimulatory and pro-inflammatory signals in human T lymphocytes (01a Articolo in rivista)
    KUNKL, MARTINA; PORCIELLO, NICLA; MASTROGIOVANNI, MARTA; CAPUANO, CRISTINA; LUCANTONI, FEDERICA; MORETTI, CHIARA; GALANDRINI, RICCIARDA; BUZZETTI, RAFFAELLA; TUOSTO, LORETTA
  • 11573/875474 - 2016 - Phosphatidylinositol 4-Phosphate 5-Kinases in the Regulation of T Cell Activation (01a Articolo in rivista)
    PORCIELLO, NICLA; KUNKL, MARTINA; TUOSTO, LORETTA
  • 11573/1115817 - 2018 - CD28 between tolerance and autoimmunity: The side effects of animal models [version 1; referees: 2 approved] (01a Articolo in rivista)
    PORCIELLO, NICLA; KUNKL, MARTINA; TUOSTO, LORETTA
  • 11573/1681026 - 2023 - Bivalent binding of staphylococcal superantigens to the TCR and CD28 triggers inflammatory signals independently of antigen presenting cells (01a Articolo in rivista)
    KUNKL, MARTINA; AMORMINO, CAROLA; SPALLOTTA, FRANCESCO; CARISTI, SILVANA; FIORILLO, MARIA TERESA; PAIARDINI, ALESSANDRO; TUOSTO, LORETTA
  • 11573/1301270 - 2019 - CD28 Autonomous Signaling Up-Regulates C-Myc Expression and Promotes Glycolysis Enabling Inflammatory T Cell Responses in Multiple Sclerosis (01a Articolo in rivista)
    KUNKL, MARTINA; RUGGIERI, SERENA; AMORMINO, CAROLA; GASPERINI, CLAUDIO; TUOSTO, LORETTA
  • 11573/1383555 - 2020 - T Helper Cells: The Modulators of Inflammation in Multiple Sclerosis (01a Articolo in rivista)
    KUNKL, MARTINA; AMORMINO, CAROLA; TUOSTO, LORETTA
  • 11573/1456992 - 2020 - CD28 autonomous signaling orchestrates IL-22 expression and IL-22-regulated epithelial barrier functions in human T lymphocytes (01a Articolo in rivista)
    KUNKL, MARTINA; AMORMINO, CAROLA; CARISTI, SILVANA; ARCIERI, STEFANO; TUOSTO, LORETTA
  • 11573/1614635 - 2022 - Astrocytes and inflammatory T Helper Cells: a dangerous liaison in Multiple Sclerosis (01a Articolo in rivista)
    KUNKL, MARTINA; AMORMINO, CAROLA; TEDESCHI, VALENTINA; FIORILLO, MARIA TERESA; TUOSTO, LORETTA
  • 11573/1625477 - 2022 - CD8+ T cell senescence: lights and shadows in viral infections, autoimmune disorders and cancer (01a Articolo in rivista)
    TEDESCHI, VALENTINA; PALDINO, GIORGIA; KUNKL, MARTINA; PAROLI, MARINO; SORRENTINO, ROSA; TUOSTO, LORETTA; FIORILLO, MARIA TERESA
  • 11573/1652973 - 2022 - SARS-CoV-2 spike does not possess intrinsic superantigen-like inflammatory activity (01a Articolo in rivista)
    AMORMINO, CAROLA; TEDESCHI, VALENTINA; PALDINO, GIORGIA; ARCIERI, STEFANO; FIORILLO, MARIA TERESA; PAIARDINI, ALESSANDRO; TUOSTO, LORETTA; KUNKL, MARTINA
  • 11573/1660843 - 2021 - CD28 individual signaling up-regulates IL-22 expression and IL-22-mediated effector functions in human T lymphocytes (04d Abstract in atti di convegno)
    KUNKL, MARTINA; AMORMINO, CAROLA; CARISTI, SILVANA; ARCIERI, STEFANO; BATTISTINI, LUIGI; TUOSTO, LORETTA
  • 11573/1333288 - 2019 - CD28 and associated class 1A P13K regulates the glycolytic metabolic program associated to pro-inflammatory T cell responses in Multiple Sclerosis (04d Abstract in atti di convegno)
    KUNKL, MARTINA; AMORMINO, CAROLA; CARISTI, SILVANA; TUOSTO, LORETTA
  • 11573/1333285 - 2019 - ReIA/NF-kB and STAT3 transcription factors cooperate in trans-activating the human IL-17A proximal promoter in response to CD28 individual stimulation (04d Abstract in atti di convegno)
    KUNKL, MARTINA; MASTROGIOVANNI, MARTA; PORCIELLO, NICLA; CARISTI, SILVANA; MONTELEONE, ELENA; ARCIERI, STEFANO; TUOSTO, LORETTA
  • 11573/1660841 - 2021 - Staphylococcal enterotoxin B (SEB) activates TCR- and CD28-mediated inflammatory signals in the absence of MHC class II molecules (04d Abstract in atti di convegno)
    KUNKL, MARTINA; AMORMINO, CAROLA; CARISTI, SILVANA; TEDESCHI, VALENTINA; FIORILLO, MARIA TERESA; TUOSTO, LORETTA
  • 11573/1268493 - 2019 - CD28 Individual Signaling Up-regulates Human IL-17A Expression by Promoting the Recruitment of RelA/NF-κB and STAT3 Transcription Factors on the Proximal Promoter (01a Articolo in rivista)
    KUNKL, MARTINA; MASTROGIOVANNI, MARTA; PORCIELLO, NICLA; CARISTI, SILVANA; ARCIERI, STEFANO; TUOSTO, LORETTA
  • 11573/1569930 - 2021 - Binding of Staphylococcal Enterotoxin B (SEB) to B7 Receptors Triggers TCR- and CD28-Mediated Inflammatory Signals in the Absence of MHC Class II Molecules (01a Articolo in rivista)
    KUNKL, MARTINA; AMORMINO, CAROLA; CARISTI, SILVANA; TEDESCHI, VALENTINA; FIORILLO, MARIA TERESA; TUOSTO, LORETTA

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