Center for Molecular Medicine Cologne

Corrado, Mauro - CAP 21

Investigating the metabolic determinants of T cell immunological memory

Introduction

How T lymphocytes establish long-term immune memory  (Figure1) has been attributed to multiple mechanisms involving prolonged cellular longevity, post-translational regulation of key proteins, and epigenetic reprogramming of the cellular transcriptome.

    In recent years, the emerging field of immunometabolism has started to unveil the role of metabolism in shaping immune function, and to reveal how modulating cell or organismal metabolism can affect immune cell differentiation. In my group at CECAD Research Center we aim at investigating how mitochondrial function is regulated in T cells in health and disease and how its dysregulation during ageing or pathology results in impaired or altered immune response. Our long-term goal is to clarify the transcriptional and microenvironmental mechanisms involved in the development of long-term immune memory and define how metabolic plasticity modulates cellular responses to stress and immune challenges.

    Research Activities

    The research in my group focuses on the role of mitochondrial metabolism, and in particular of cardiolipin (the distinctive inner mitochondrial membrane phospholipid), in shaping immunity, inflammation, and ageing. The importance of cardiolipin in mitochondrial function is evidenced not just by the X-linked inherited pathology Barth syndrome, a result of cardiolipin remodeling deficiency but also by its role in many conditions ranging from neurodegeneration to traumatic brain injury, from multiple sclerosis to heart failure. Yet we understand little about how CL alterations cause, participate or exacerbate these conditions beyond regulating OXPHOS efficiency.
    We have showed how the dynamic synthesis and remodeling of cardiolipin is responsible for the metabolic and functional plasticity of CD8+ T cells during an immune response (Figure 2-3) (Corrado et al., 2020).

      Our research also highlights CD8+ lymphopenia and functional impairments as previously uncharacterized features of Barth syndrome, where patients have Tafazzin mutations and so defective cardiolipin remodeling. Moreover, our recent work on the metabolic regulation of thymic development has shown how metabolism influences the immune system starting from the developmental stage (Corrado et al., 2021). This is important because one of the first manifestations of ageing is thymic involution. Our work shows how mitochondrial respiration impairment has long-lasting consequences on immune function and immune memory development.

      Clinical Relevance

      In our lab, we aim at better understanding how metabolism impacts immune function in ageing, cancer or infections. The acquired knowledge about basic metabolic and signaling circuits in T cells in these conditions will lead us to harness those same pathways to improve disease prevention, treatment and outcome. Thus, our approach on immunometabolism reveals an extraordinary translational potential. In particular, our research plan has clear clinical relevance in the following three directions:

      • Patients affected by mitochondrial diseases (MDs) also show immune defects linking systemic metabolism to immune function alteration (Corrado and Pearce, 2022). Up to half of the patients with MDs experience recurrent or severe upper respiratory tract infections, often resulting in life-threatening conditions. This percentage increases to almost 90% of pediatric MD patients. We have a specific interest in defining the immune and inflammatory landscape of patients affected by Barth Syndrome, characterized by mutations in the acyltransferase Tafazzin responsible for the process of cardiolipin remodeling.
      • Establishing long-term immune memory able to recognize and fight previously encountered antigens is central to the success of any vaccination campaigns or cancer immunotherapy. Nevertheless, the mechanisms underlying induction and maintenance of immunological memory still remain elusive. Our line of research aims at identifying and characterize metabolic checkpoint to be exploited in cancer immunotherapy or to improve current and future vaccine regimens.
      • Mitochondria are central hub for inflammatory signals with (among other mechanisms) the release of mitochondrial DNA – mtDNA – to the cytoplasm or the relocalization of cardiolipin to the outer mitochondrial membrane resulting in the activation of strong pro-inflammatory cascades culminating in the expression of Type I Interferons and IL-1β (Figure 4). In our lab, multiple projects aim at defining in vivo the contribution of mitochondrial defects to inflammation.

      Our Aims

      Overall, these observations show the functional nuances of metabolism in T cell immunity suggesting that modulation of cellular or organismal metabolism influence directly immune function. They also imply a possible partially immunocompromised condition in patients affected by mitochondrial diseases (both in terms of immune response to pathogens and vaccines) and open important questions:

      • How does mitochondrial fitness regulate T cell differentiation and function?
      • Which metabolic and signaling rewiring mechanisms are driven by mitochondrial deficiencies in T cells?
      • How do mitochondrial deficiencies modulate inflammation?

      Starting from these questions, our research program to further delve into T cell biology and physiology when mitochondrial metabolism is altered.

      • *Corrado M, Pearce EL: Targeting memory T cell metabolism to improve immunity, The Journal of Clinical Investigation (2022); 132: 1. *Corresponding author
      • *Corrado M, Samardzic D, Giacomello M, Rana N, Pearce EL, *Scorrano L: Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism. Cell Death and Differentiation (2021); 28: 2194-2206. *Corresponding author
      • Corrado M, Edwards-Hicks J, Villa M, Flachsmann LJ, Sanin DE, Jacobs M, Baixauli F, Stanczak M, Anderson E, Azuma M, Quintana A, Curtis JD, Clapes T, Grzes KM, Kabat AM, Kyle R, Patterson AE, Klein Geltink RI, Amulic B, Steward CG, Strathdee D, Trompouki E, O’Sullivan D, Pearce EJ, Pearce EL: Dynamic cardiolipin synthesis is required for CD8+ T cell immunity. Cell Metabolism (2020); 32 (6): 981-995. e7.
      • *Simula L, *Corrado M, Accordi B, Di Rita A, Nazio F, Antonucci Y, Di Daniele A, Caicci F, Caruana I, Soriano ME, Pigazzi M, Locatelli F, Cecconi F, Campello S: JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction. Cell Death and Differentiation (2020); 27: 2749-2767. *Equal contribution
      • Quintana-Cabrera R, Quirin C, Glytsou C, Corrado M, Urbani A, Pellattiero A, Calvo E, Vázquez J, Enríquez JA, Gerle C, Soriano ME, Bernardi P, Scorrano L: The cristae modulator Optic atrophy 1 requires mitochondrial ATP synthase oligomers to safeguard mitochondrial function. Nature Communications (2018); 9 (1): 1-13.
      • Klein Geltink RI, O’Sullivan D, Corrado M, Bremser A, Buck MD, Buescher JM, Firat E, Zhu X, Nie-dermann G, Caputa G, Kelly B, Warthorst U, Rensing-Ehl A, Kyle RL, Vandersarren L, Curtis JD, Pat-terson AE, Lawless S, Grzes K, Qiu J, Sanin DE, Kretz O, Huber TB, Janssens S, Lambrecht BN, Ram-bold AS, Pearce EJ, Pearce EL: Mitochondrial priming by CD28. Cell (2017); 171 (2): 385-397 .e11
      • Corrado M, Mariotti FR, Trapani L, Taraborrelli L, Nazio F, Cianfanelli V, Soriano ME, Schrepfer E, Cecconi F, Scorrano L, Campello S: Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis. EMBO Journal (2016); 35 (16): 1793-1809.
      • Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Ca-sarin A, Gomes LG, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L: Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respirato-ry efficiency. Cell (2013); 155 (1): 160-171.

      *Corrado M, Pearce EL: Targeting memory T cell metabolism to improve immunity, The Journal of Clinical Investigation (2022); 132: 1. *Corresponding author

      • *Corrado M, Samardzic D, Giacomello M, Rana N, Pearce EL, *Scorrano L: Deletion of the mitochondria-shaping protein Opa1 during early thymocyte maturation impacts mature memory T cell metabolism. Cell Death and Differentiation (2021); 28: 2194-2206. *Corresponding author
      • Puleston DJ, Baixauli F, Sanin DE, Edwards-Hicks J, Villa M, Kabat AM, Kamiński MM, Stanckzak M, Weiss HJ, Grzes KM, Piletic K, Field CS, Corrado M, Haessler F, Wang C, Musa Y, Schimmelpfennig L, Flachsmann L, Mittler G, Yosef N, Kuchroo VK, Buescher JM, Balabanov S, Pearce EJ, Green DR, Pearce EL: Polyamine metabolism is a central determinant of helper T cell lineage fidelity. Cell. (2021); 184 (16): 4186-4202.e20.
      • O'Sullivan D, Stanczak MA, Villa M, Uhl FM, Corrado M, Klein Geltink RI, Sanin DE, Apostolova P, Rana N, Edwards-Hicks J, Grzes KM, Kabat AM, Kyle RL, Fabri M, Curtis JD, Buck MD, Patterson AE, Regina A, Field CS, Baixauli F, Puleston DJ, Pearce EJ, Zeiser R, Pearce EL: Fever supports CD8+ effector T cell responses by promoting mitochondrial translation. Proc Natl Acad Sci U S A. (2021); 118 (25): e2023752118
      • Quintana-Cabrera R, Manjarrés-Raza I, Vicente-Gutiérrez C, Corrado M, Bolaños JP, Scorrano L: Opa1 relies on cristae preservation and ATP synthase to curtail reactive oxygen species accumula-tion in mitochondria. Redox biology (2021); 41: 101944
      • Fabri M, Villa M, Stanczak MA, Edwards-Hicks J, Corrado M, Pearce EL: Research Techniques Made Simple: Profiling Cellular Energy Metabolism, Journal of Investigative Dermatology (2021); 141 (12): 2767-2774. e2
      • Corrado M, Edwards-Hicks J, Villa M, Flachsmann LJ, Sanin DE, Jacobs M, Baixauli F, Stanczak M, Anderson E, Azuma M, Quintana A, Curtis JD, Clapes T, Grzes KM, Kabat AM, Kyle R, Patterson AE, Klein Geltink RI, Amulic B, Steward CG, Strathdee D, Trompouki E, O’Sullivan D, Pearce EJ, Pearce EL: Dynamic cardiolipin synthesis is required for CD8+ T cell immunity. Cell Metabolism (2020); 32 (6): 981-995. e7.
      • *Simula L, *Corrado M, Accordi B, Di Rita A, Nazio F, Antonucci Y, Di Daniele A, Caicci F, Caruana I, Soriano ME, Pigazzi M, Locatelli F, Cecconi F, Campello S: JNK1 and ERK1/2 modulate lymphocyte homeostasis via BIM and DRP1 upon AICD induction. Cell Death and Differentiation (2020); 27: 2749-2767. *Equal contribution
      • Kapoor T, Corrado M, Pearce EL, Pearce EJ, Grosschedl R: MZB1 enables efficient interferon α secretion in stimulated plasmacytoid dendritic cells. Scientific Reports (2020); 10 (1): 1-11
      • Castoldi A, Monteiro LB, van Teijlingen Bakker N, Sanin DE, Rana N, Corrado M, Cameron AM, Hässler F, Matsushita M, Caputa G, Klein Geltink RI, Büscher J, Edwards-Hicks J, Pearce EL, Pearce EJ: Triacylglycerol synthesis enhances macrophage inflammatory function. Nature communications (2020); 11 (1): 1-11
      • Field CS, Baixauli F, Kyle RL, Puleston DJ, Cameron AM, Sanin DE, Hippen KL, Loschi M, Thangavelu G, Corrado M, Edwards-Hicks J, Grzes KM, Pearce EJ, Blazar BR, Pearce EL: Mitochondrial Integrity Regulated by Lipid Metabolism Is a Cell-Intrinsic Checkpoint for Treg Suppressive Function. Cell Metab (2020); 31(2):422-437.e5.
      • Puleston DJ, Buck MD, Klein Geltink RI, Kyle RL, Caputa G, O’Sullivan D, Cameron AM, Castoldi A, Musa Y, Kabat AM, Zhang Y, Flachsmann LJ, Field CS, Patterson AE, Scherer S, Alfei F, Baixauli F, Austin SK, Kelly B, Matsushita M, Curtis JD, Grzes KM, Villa M, Corrado M, Sanin DE, Qiu J, Pällman N, Paz K, Maccari ME, Blazar BR, Mittler G, Buescher JM, Zehn D, Rospert S, Pearce EJ, Balabanov S, Pearce EL: Polyamines and eIF5A hypusination modulate mitochondrial respiration and macrophage activation. Cell Metabolsim (2019); 30 (2): 352-363. e8
      • Qiu J, Villa M, Sanin DE, Buck MD, O'Sullivan D, Ching R, Matsushita M, Grzes KM, Winkler F, Chang CH, Curtis JD, Kyle RL, Van Teijlingen Bakker N, Corrado M, Haessler F, Alfei F, Edwards-Hicks J, Maggi LB Jr, Zehn D, Egawa T, Bengsch B, Klein Geltink RI, Jenuwein T, Pearce EJ, Pearce EL: Acetate Promotes T Cell Effector Function during Glucose Restriction. Cell Rep. (2019); 27(7):2063-2074.e5.

      Sanin DE, Matsushita M, Klein Geltink RI, Grzes KM, van Teijlingen Bakke Nr, Corrado M, Kabat AM, Buck MD, Qiu J, Lawless SJ, Cameron AM, Villa M, Baixauli F, Patterson AE, Hässler F, Curtis JD, O’Neill CM, O’Sullivan D, Wu D, Mittler G, Ching-Cheng Huang S, Pearce EL, Pearce EJ: Mitochondrial membrane potential regulates nuclear gene expression in macrophages exposed to prostaglandin E2. Immunity (2018); 49 (60): 1021-1033. e6

      Simula L, Pacella I, Colamatteo A, Procaccini C, Cancila V, BordI M, Tregnago C, Corrado M, Pigazzi M, Barnaba V, Tripodo C, Matarese G, Piconese S, Campello S: Drp1 controls effective T cell immune-surveillance by regulating T cell migration, proliferation, and cMyc-dependent metabolic reprogramming. Cell reports (2018); 25 (11): 3059-3073. e10

      Klein Geltink RI, O’Sullivan D, Corrado M, Bremser A, Buck MD, Buescher JM, Firat E, Zhu X, Nie-dermann G, Caputa G, Kelly B, Warthorst U, Rensing-Ehl A, Kyle RL, Vandersarren L, Curtis JD, Pat-terson AE, Lawless S, Grzes K, Qiu J, Sanin DE, Kretz O, Huber TB, Janssens S, Lambrecht BN, Ram-bold AS, Pearce EJ, Pearce EL: Mitochondrial priming by CD28. Cell (2017); 171 (2): 385-397 .e11

      Corrado M, Mariotti FR, Trapani L, Taraborrelli L, Nazio F, Cianfanelli V, Soriano ME, Schrepfer E, Cecconi F, Scorrano L, Campello S: Macroautophagy inhibition maintains fragmented mitochondria to foster T cell receptor-dependent apoptosis. EMBO Journal (2016); 35 (16): 1793-1809.

      Corrado M, Campello S: Autophagy inhibition and mitochondrial remodeling join forces to amplify apoptosis in activation-induced cell death. Autophagy (2016); 12 (12), 2496-2497

      Corrado M, Scorrano L, Campello S: Changing perspective on oncometabolites: from metabolic signature of cancer to tumorigenic and immunosuppressive agents. Oncotarget (2016); 7 (29): 46692

      • Cogliati S, Frezza C, Soriano ME, Varanita T, Quintana-Cabrera R, Corrado M, Cipolat S, Costa V, Ca-sarin A, Gomes LG, Perales-Clemente E, Salviati L, Fernandez-Silva P, Enriquez JA, Scorrano L: Mitochondrial cristae shape determines respiratory chain supercomplexes assembly and respirato-ry efficiency. Cell (2013); 155 (1): 160-171.
      • Corrado M, Scorrano L, Campello S: Mitochondrial dynamics in cancer and neurodegenerative and neuroinflammatory diseases. International Journal of Cell Biology (2012); 729290.
      • Strappazzon F, Nazio F, Corrado M, Cianfanelli V, Romagnoli A, Fimia GM, Campello S, Nardacci R, Piacentini M, Campanella M, Cecconi F: AMBRA1 is able to induce mitophagy via LC3 binding, regardless of PARKIN and p62/SQSTM1. Cell death and differentiation (2015); 22 (3): 419-432
      • Di Giacomo G, Campello S, Corrado M, Di Giambattista l, Cirotti C, Filomeni G, Gentile G: Mature erythrocytes of Iguana iguana (Squamata, Iguanidae) possess functional mitochondria. Plos One (2015); 10 (9): e0136770
      • Mariotti FR, Corrado M, Campello S: Following mitochondria dynamism: confocal analysis of the organelle morphology. Mitochondrial Regulation (2015); 153-161
      Dr. Mauro Corrado CMMC Cologne
      Dr. Mauro Corrado

      CECAD Research Center

      CMMC - PI - CAP 21

      +49 221 478 84167

      CECAD Research Center

      Joseph-Stelzmann-Str. 26

      50931 Cologne

      CMMC Profile Page

      Curriculum Vitae (CV)

      Publications - Mauro Corrado

      Link to PubMed

      Affiliations
      Group Members

      Regina Annamaria, PhD student
      Sara Gjurgji, PhD student
      Irma Alibashikj, Master student
      Elena Potenza, Erasmus+ student