[en] Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7/DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases.
Disciplines :
Life sciences: Multidisciplinary, general & others
Author, co-author :
Zeng, Ni ✱; Luxembourg Institute of Health - LIH > Department of Infection and Immunity ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM)
Capelle, Christophe M. ✱; Luxembourg Institute of Health - LIH > Department of Infection and Immunity ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM)
BARON, Alexandre ; Luxembourg Institute of Health - LIH > Department of Infection and Immunity
KOBAYASHI, Takumi ; Luxembourg Institute of Health - LIH > Department of Infection and Immunity
Cire, Severine; Luxembourg Institute of Health - LIH > Department of Infection and Immunity
TSLAF, Vera ; Luxembourg Institute of Health - LIH > Department of Infection and Immunity ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) ; Luxembourg Institute of Health - LIH > Transversal Translational Medicine
Leonard, Cathy; Luxembourg Institute of Health - LIH > Department of Infection and Immunity
COOWAR, Djalil ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Scientific Central Services
Koseki, Haruhiko; RIKEN Center for Integrative Medical Sciences > Laboratory for Developmental Genetics ; Japanese Agency for Medical Research and Development > AMED-CREST
Westendorf, Astrid M.; University Duisburg-Essen, University Hospital Essen > Institute of Medical Microbiology
Buer, Jan; University Duisburg-Essen, University Hospital Essen > Institute of Medical Microbiology
BRENNER, Dirk ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Immunology and Genetics ; Luxembourg Institute of Health - LIH > Department of Infection and Immunity
KRÜGER, Rejko ; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) > Translational Neuroscience ; Luxembourg Institute of Health - LIH > Transversal Translational Medicine ; Centre Hospitalier de Luxembourg - CHL
Balling, Rudi; University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB)
OLLERT, Markus ; Luxembourg Institute of Health - LIH > Department of Infection and Immunity ; University of Southern Denmark, Odense Research Center for Anaphylaxis - ORCA > Department of Dermatology and Allergy Center
HE, Feng ; Luxembourg Institute of Health - LIH > Department of Infection and Immunity ; University Duisburg-Essen, University Hospital Essen > Institute of Medical Microbiology
Ahmed M, Lanzer KG, Yager EJ, Adams PS, Johnson LL, Blackman MA (2009) Clonal expansions and loss of receptor diversity in the naive CD8 T cell repertoire of aged mice. J Immunol 182: 784–792
Ahn E, Araki K, Hashimoto M, Li W, Riley JL, Cheung J, Sharpe AH, Freeman GJ, Irving BA, Ahmed R (2018) Role of PD-1 during effector CD8 T cell differentiation. Proc Natl Acad Sci USA 115: 4749–4754
Akbar AN, Gilroy DW (2020) Aging immunity may exacerbate COVID-19. Science 369: 256–257
Akbar AN, Henson SM (2011) Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat Rev Immunol 11: 289–295
Aw D, Silva AB, Palmer DB (2007) Immunosenescence: emerging challenges for an ageing population. Immunology 120: 435–446
Bandres E, Merino J, Vazquez B, Inoges S, Moreno C, Subira ML, Sanchez-Ibarrola A (2000) The increase of IFN-gamma production through aging correlates with the expanded CD8(+high)CD28(-)CD57(+) subpopulation. Clin Immunol 96: 230–235
Boussaad I, Obermaier CD, Hanss Z, Bobbili DR, Bolognin S, Glaab E, Wołyńska K, Weisschuh N, De Conti L, May C et al (2020) A patient-based model of RNA mis-splicing uncovers treatment targets in Parkinson's disease. Sci Transl Med 12: eaau3960
Braun J, Loyal L, Frentsch M, Wendisch D, Georg P, Kurth F, Hippenstiel S, Dingeldey M, Kruse B, Fauchere F et al (2020) SARS-CoV-2-reactive T cells in healthy donors and patients with COVID-19. Nature 587: 270–274
Brunner S, Herndler-Brandstetter D, Weinberger B, Grubeck-Loebenstein B (2011) Persistent viral infections and immune aging. Ageing Res Rev 10: 362–369
Burbulla LF, Song P, Mazzulli JR, Zampese E, Wong YC, Jeon S, Santos DP, Blanz J, Obermaier CD, Strojny C et al (2017) Dopamine oxidation mediates mitochondrial and lysosomal dysfunction in Parkinson's disease. Science 357: 1255–1261
Capelle CM, Zeng N, Danileviciute E, Rodrigues SF, Ollert M, Balling R, He FQ (2021) Identification of VIMP as a gene inhibiting cytokine production in human CD4+ effector T cells. iScience 24: 102289
Cavanagh MM, Qi Q, Weyand CM, Goronzy JJ (2011) Finding balance: T cell regulatory receptor expression during aging. Aging Dis 2: 398–413
CDC (2019) People 65 years and older & influenza
Chiu BC, Martin BE, Stolberg VR, Chensue SW (2013) Cutting edge: central memory CD8 T cells in aged mice are virtual memory cells. J Immunol 191: 5793–5796
Cho BK, Rao VP, Ge Q, Eisen HN, Chen J (2000) Homeostasis-stimulated proliferation drives naive T cells to differentiate directly into memory T cells. J Exp Med 192: 549–556
Crane JD, Devries MC, Safdar A, Hamadeh MJ, Tarnopolsky MA (2009) The effect of aging on human skeletal muscle mitochondrial and intramyocellular lipid ultrastructure. J Gerontol 65A: 119–128
Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ, Ouslander JG, Weyand CM, Goronzy JJ (2008) T cell subset-specific susceptibility to aging. Clin Immunol 127: 107–118
Danileviciute E, Zeng N, Capelle C, Paczia N, Gillespie MA, Kurniawan H, Coowar D, Vogt Weisenhorn DM, Giro GG, Grusdat M et al (2019) PARK7/DJ-1 promotes pyruvate dehydrogenase activity and maintains Treg homeostasis. bioRxiv https://doi.org/10.1101/2019.12.20.884809 [PREPRINT]
Desdín-Micó G, Soto-Heredero G, Aranda JF, Oller J, Carrasco E, Gabandé-Rodríguez E, Blanco EM, Alfranca A, Cussó L, Desco M et al (2020) T cells with dysfunctional mitochondria induce multimorbidity and premature senescence. Science 368: 1371–1376
Egorov ES, Kasatskaya SA, Zubov VN, Izraelson M, Nakonechnaya TO, Staroverov DB, Angius A, Cucca F, Mamedov IZ, Rosati E et al (2018) The changing landscape of naive T cell receptor repertoire with human aging. Front Immunol 9: 1618
Ferrucci L, Fabbri E (2018) Inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty. Nat Rev Cardiol 15: 505–522
Flurkey KM, Currer J, Harrison DE (2007) Chapter 20 - mouse models in aging research. In The mouse in biomedical research (Second Edition), Fox JG, Davisson MT, Quimby FW, Barthold SW, Newcomer CE, Smith AL (eds), pp 637–672. Burlington: Academic Press
Fulop T, Larbi A, Pawelec G (2013) Human T cell aging and the impact of persistent viral infections. Front Immunol 4: 271
Goronzy JJ, Weyand CM (2013) Understanding immunosenescence to improve responses to vaccines. Nat Immunol 14: 428–436
Goronzy JJ, Weyand CM (2019) Mechanisms underlying T cell ageing. Nat Rev Immunol 19: 573–583
Henson SM, Lanna A, Riddell NE, Franzese O, Macaulay R, Griffiths SJ, Puleston DJ, Watson AS, Simon AK, Tooze SA et al (2014) p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8+ T cells. J Clin Invest 124: 4004–4016
Huang DW, Sherman BT, Lempicki RA (2008) Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat Protoc 4: 44
Hwang AB, Jeong DE, Lee SJ (2012) Mitochondria and organismal longevity. Curr Genomics 13: 519–532
Jung SH, Won KJ, Lee KP, Lee DH, Yu S, Lee D-Y, Seo E-H, Kang H, Park E-S, Kim H-J et al (2014) DJ-1 protein regulates CD3+ T cell migration via overexpression of CXCR4 receptor. Atherosclerosis 235: 503–509
Junge S, Kloeckener-Gruissem B, Zufferey R, Keisker A, Salgo B, Fauchere J-C, Scherer F, Shalaby T, Grotzer M, Siler U et al (2007) Correlation between recent thymic emigrants and CD31+ (PECAM-1) CD4+ T cells in normal individuals during aging and in lymphopenic children. Eur J Immunol 37: 3270–3280
Kimmig S, Przybylski GK, Schmidt CA, Laurisch K, Möwes B, Radbruch A, Thiel A (2002) Two subsets of naive T helper cells with distinct T cell receptor excision circle content in human adult peripheral blood. J Exp Med 195: 789–794
Lanna A, Gomes DC, Muller-Durovic B, McDonnell T, Escors D, Gilroy DW, Lee JH, Karin M, Akbar AN (2017) A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat Immunol 18: 354–363
Lee KA, Shin KS, Kim GY, Song YC, Bae EA, Kim IK, Koh CH, Kang CY (2016) Characterization of age-associated exhausted CD8(+) T cells defined by increased expression of Tim-3 and PD-1. Aging Cell 15: 291–300
Liu X, Jiang N, Hughes B, Bigras E, Shoubridge E, Hekimi S (2005) Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes Dev 19: 2424–2434
Mannick JB, Del Giudice G, Lattanzi M, Valiante NM, Praestgaard J, Huang B, Lonetto MA, Maecker HT, Kovarik J, Carson S et al (2014) mTOR inhibition improves immune function in the elderly. Sci Transl Med 6: 268ra179
Masopust D, Vezys V, Marzo AL, Lefrancois L (2001) Preferential localization of effector memory cells in nonlymphoid tissue. Science 291: 2413–2417
Minato N, Hattori M, Hamazaki Y (2020) Physiology and pathology of T-cell aging. Int Immunol 32: 223–231
Mogilenko DA, Shpynov O, Andhey PS, Arthur L, Swain A, Esaulova E, Brioschi S, Shchukina I, Kerndl M, Bambouskova M et al (2021) Comprehensive profiling of an aging immune system reveals clonal GZMK(+) CD8(+) T cells as conserved hallmark of inflammaging. Immunity 54: 99–115.e12
National Institute on Aging, National Institutes of Health, World Health Organization (WHO) (2011) Global health and aging, NIH Publication no. 11-7737
Newman DK, Fu G, McOlash L, Schauder D, Newman PJ, Cui W, Rao S, Johnson BD, Gershan JA, Riese MJ (2018) Frontline Science: PECAM-1 (CD31) expression in naive and memory, but not acutely activated, CD8(+) T cells. J Leukoc Biol 104: 883–893
Niccoli T, Partridge L (2012) Ageing as a risk factor for disease. Curr Biol 22: R741–752
Nikolich-Zugich J (2008) Ageing and life-long maintenance of T-cell subsets in the face of latent persistent infections. Nat Rev Immunol 8: 512–522
Nikolich-Žugich J (2018) The twilight of immunity: emerging concepts in aging of the immune system. Nat Immunol 19: 10–19
O'Sullivan D, Pearce EL (2015) Targeting T cell metabolism for therapy. Trends Immunol 36: 71–80
Pankratz N, Pauciulo MW, Elsaesser VE, Marek DK, Halter CA, Wojcieszek J, Rudolph A, Shults CW, Foroud T, Nichols WC et al (2006) Mutations in DJ-1 are rare in familial Parkinson disease. Neurosci Lett 408: 209–213
Pawelec G, Derhovanessian E (2011) Role of CMV in immune senescence. Virus Res 157: 175–179
Pereira BI, De Maeyer RPH, Covre LP, Nehar-Belaid D, Lanna A, Ward S, Marches R, Chambers ES, Gomes DCO, Riddell NE et al (2020) Sestrins induce natural killer function in senescent-like CD8+ T cells. Nat Immunol 21: 684–694
Pham TT, Giesert F, Röthig A, Floss T, Kallnik M, Weindl K, Hölter SM, Ahting U, Prokisch H, Becker L et al (2010) DJ-1-deficient mice show less TH-positive neurons in the ventral tegmental area and exhibit non-motoric behavioural impairments. Genes Brain Behav 9: 305–317
Picca A, Mankowski RT, Burman JL, Donisi L, Kim J-S, Marzetti E, Leeuwenburgh C (2018) Mitochondrial quality control mechanisms as molecular targets in cardiac ageing. Nat Rev Cardiol 15: 543–554
Pieren DKJ, Smits NAM, van de Garde MDB, Guichelaar T (2019) Response kinetics reveal novel features of ageing in murine T cells. Sci Rep 9: 5587
Pontzer H, Raichlen DA, Gordon AD, Schroepfer-Walker KK, Hare B, O'Neill MC, Muldoon KM, Dunsworth HM, Wood BM, Isler K et al (2014) Primate energy expenditure and life history. Proc Natl Acad Sci USA 111: 1433–1437
Qi Q, Liu Y, Cheng Y, Glanville J, Zhang D, Lee JY, Olshen RA, Weyand CM, Boyd SD, Goronzy JJ (2014) Diversity and clonal selection in the human T-cell repertoire. Proc Natl Acad Sci USA 111: 13139–13144
Quinn KM, Fox A, Harland KL, Russ BE, Li J, Nguyen THO, Loh L, Olshanksy M, Naeem H, Tsyganov K et al (2018) Age-related decline in primary CD8(+) T cell responses is associated with the development of senescence in virtual memory CD8(+) T cells. Cell Rep 23: 3512–3524
Quinn KM, Hussain T, Kraus F, Formosa LE, Lam WK, Dagley MJ, Saunders EC, Assmus LM, Wynne-Jones E, Loh L et al (2020) Metabolic characteristics of CD8+ T cell subsets in young and aged individuals are not predictive of functionality. Nat Commun 11: 2857
Raynor J, Lages CS, Shehata H, Hildeman DA, Chougnet CA (2012) Homeostasis and function of regulatory T cells in aging. Curr Opin Immunol 24: 482–487
Rudd BD, Venturi V, Li G, Samadder P, Ertelt JM, Way SS, Davenport MP, Nikolich-Zugich J (2011) Nonrandom attrition of the naive CD8+ T-cell pool with aging governed by T-cell receptor:pMHC interactions. Proc Natl Acad Sci USA 108: 13694–13699
Sansoni P, Vescovini R, Fagnoni FF, Akbar A, Arens R, Chiu Y-L, Čičin-Šain L, Dechanet-Merville J, Derhovanessian E, Ferrando-Martinez S et al (2014) New advances in CMV and immunosenescence. Exp Gerontol 55: 54–62
Spaulding C, Guo W, Effros RB (1999) Resistance to apoptosis in human CD8+ T cells that reach replicative senescence after multiple rounds of antigen-specific proliferation. Exp Gerontol 34: 633–644
Tanaskovic S, Fernandez S, Price P, Lee S, French MA (2010) CD31 (PECAM-1) is a marker of recent thymic emigrants among CD4+ T-cells, but not CD8+ T-cells or gammadelta T-cells, in HIV patients responding to ART. Immunol Cell Biol 88: 321–327
Vrisekoop N, den Braber I, de Boer AB, Ruiter AFC, Ackermans MT, van der Crabben SN, Schrijver EHR, Spierenburg G, Sauerwein HP, Hazenberg MD et al (2008) Sparse production but preferential incorporation of recently produced naive T cells in the human peripheral pool. Proc Natl Acad Sci USA 105: 6115–6120
Wilson MA (2011) The role of cysteine oxidation in DJ-1 function and dysfunction. Antioxid Redox Signal 15: 111–122
van der Windt GJW, Everts B, Chang CH, Curtis JD, Freitas TC, Amiel E, Pearce EJ, Pearce EL (2012) Mitochondrial respiratory capacity is a critical regulator of CD8+ T cell memory development. Immunity 36: 68–78
van der Windt GJ, Pearce EL (2012) Metabolic switching and fuel choice during T-cell differentiation and memory development. Immunol Rev 249: 27–42
Xu W, Larbi A (2017) Markers of T cell senescence in humans. Int J Mol Sci 18: 1742
Yosef N, Shalek AK, Gaublomme JT, Jin H, Lee Y, Awasthi A, Wu C, Karwacz K, Xiao S, Jorgolli M et al (2013) Dynamic regulatory network controlling TH17 cell differentiation. Nature 496: 461–468
Zhang L, Romero P (2018) Metabolic control of CD8+ T cell fate decisions and antitumor immunity. Trends Mol Med 24: 30–48
