Skip to main content

Advertisement

SpringerLink
Log in

Immunomodulatory role of high-density lipoproteins: impact on immunosenescence

  • Published:
AGE Aims and scope Submit manuscript

Abstract

Natural aging is accompanied by a dysregulation of the host immune response that has well-known clinical consequences but poorly defined underlying causes. It has previously been reported that advancing age is associated with an increase in membrane cholesterol level in T cells. The aim of this study was to investigate whether high-density lipoprotein (HDL) can modulate the age-related accumulation of membrane cholesterol in T cells and impact on their subsequent responsiveness. Our data reveal that cholesterol metabolism, influx, and efflux are altered in T cells with aging, which may in part explain the increase in membrane cholesterol level observed in T cells in elderly individuals. HDL was unable to promote reverse cholesterol transport in T cells from elderly subjects with the same efficiency as was observed in T cells from young subjects besides unchanged ABCA-1 and SR-BI expressions. HDL exhibited a short-acting co-stimulatory effect by enhancing T cell production of interleukin-2 (IL-2). Moreover, HDL from healthy normolipemic individuals exerted differential effects on T cell proliferation that depended on the age of the HDL donor. Finally, HDL modulated TCR/CD28 activation by inducing sustained signaling through pLck, pERK, and pAkt. These data suggest that HDL has immunomodulatory effects on T cells that are influenced by age.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Badimon L, Vilahur G (2012) LDL-cholesterol versus HDL-cholesterol in the atherosclerotic plaque: inflammatory resolution versus thrombotic chaos. Ann N Y Acad Sci 1254:18–32

    Article  PubMed  CAS  Google Scholar 

  • Berrougui H, Khalil A (2009) Age-associated decrease of high-density lipoprotein-mediated reverse cholesterol transport activity. Rejuvenation Res 12:117–26

    Article  PubMed  CAS  Google Scholar 

  • Berrougui H, Isabelle M, Cloutier M, Grenier G, Khalil A (2007) Age-related impairment of HDL-mediated cholesterol efflux. J Lipid Res 48:328–36

    Article  PubMed  CAS  Google Scholar 

  • Berrougui H, Grenier G, Loued S, Drouin G, Khalil A (2009) A new insight into resveratrol as an atheroprotective compound: inhibition of lipid peroxidation and enhancement of cholesterol efflux. Atherosclerosis 207:420–7

    Article  PubMed  CAS  Google Scholar 

  • Borba EF, Carvalho JF, Bonfá E (2006) Mechanisms of dyslipoproteinemias in systemic lupus erythematosus. Clin Dev Immunol 13:203–208

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Carpintero R, Gruaz L, Brandt KJ, Scan A, Faill D, Combes V, Grau GE, Burger D (2010) HDL interfere with the binding of T cell microparticles to human monocytes to inhibit pro-inflammatory cytokine production. PLoS One 5:e11869

    Article  PubMed  PubMed Central  Google Scholar 

  • Coetzee GA, Strachan AF, van der Westhuyzen DR, Hoppe HC, Jeenah MS, de Beer FC (1986) Serum amyloid A-containing human high density lipoprotein 3. Density, size, and apolipoprotein composition. J Biol Chem 261:9644–9651

    PubMed  CAS  Google Scholar 

  • de Mello CV, Nguyen D, Giri B, Bunbury A, Schaffer E, Taub DD (2004) Quantitative differences in lipid raft components between murine CD4+ and CD8+ T cells. BMC Immunol 5:2

    Article  Google Scholar 

  • Di Mitri D, Azevedo RI, Henson SM, Libri V, Riddell NE, Macaulay R, Kipling D, Soares MV, Battistini L, Akbar AN (2011) Reversible senescence in human CD4+CD45RA+CD27- memory T cells. J Immunol 187:2093–2100

    Article  PubMed  Google Scholar 

  • Douziech N, Seres I, Larbi A, Szikszay E, Roy PM, Arcand M, Dupuis G, Fulop T (2002) Modulation of human lymphocyte proliferative response with aging. Exp Gerontol 37:369–87

    Article  PubMed  CAS  Google Scholar 

  • Fortin CF, Larbi A, Lesur O, Douziech N, Fulop T (2006) Impairment of SHP-1 down-regulation in the lipid rafts of human neutrophils under GM-CSF stimulation contributes to their age-related, altered functions. J Leukoc Biol 79:1061–72

    Article  PubMed  CAS  Google Scholar 

  • Franceschi C, Bonafè M, Valensin S, Olivieri F, De Luca M, Ottaviani E, De Benedictis G (2000) Inflamm-aging. An evolutionary perspective on immunosenescence. Ann N Y Acad Sci 908:244–254

    Article  PubMed  CAS  Google Scholar 

  • Fülöp T, Gagné D, Goulet AC, Desgeorges S, Lacombe G, Arcand M, Dupuis G (1999) Age-related impairment of p56lck and ZAP-70 activities in human T lymphocytes activated through the TcR/CD3 complex. Exp Gerontol 34:197–216

    Article  PubMed  Google Scholar 

  • Fülöp T, Douziech N, Goulet AC, Desgeorges S, Linteau A, Lacombe G, Dupuis G (2001) Cyclodextrin modulation of T lymphocyte signal transduction with aging. Mech Ageing Dev 122:1413–1430

    Article  PubMed  Google Scholar 

  • Fulop T, Larbi A, Wikby A, Mocchegiani E, Hirokawa K, Pawelec G (2005) Dysregulation of T-cell function in the elderly: scientific basis and clinical implications. Drugs Aging 22:589–603

    Article  PubMed  Google Scholar 

  • Fülöp T, Le Page A, Garneau H, Azimi N, Baehl S, Dupuis G, Pawelec G, Larbi A (2012) Aging, immunosenescence and membrane rafts: the lipid connection. Longevity and Healthspan. MS ID : 1582891234741859

  • Fülöp T, Larbi A, Pawelec G (2013) Human T cell aging and the impact of persistent viral infections. Front Immunol 4:271

    Article  PubMed  PubMed Central  Google Scholar 

  • Fulop T, Le Page A, Fortin C, Witkowski JM, Dupuis G, Larbi A (2014) Cellular signaling in the aging immune system. Curr Opin Immunol 29C:105–111

    Article  Google Scholar 

  • Goronzy JJ, Li G, Yu M, Weyand CM (2012) Signaling pathways in aged T cells—a reflection of T cell differentiation, cell senescence and host environment. Semin Immunol 24:365–372

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Gruaz L, Delucinge-Vivier C, Descombes P, Dayer JM, Burger D (2010) Blockade of T cell contact-activation of human monocytes by high-density lipoproteins reveals a new pattern of cytokine and inflammatory genes. PLoS One 5:e9418

    Article  PubMed  PubMed Central  Google Scholar 

  • Jaouad L, de Guise C, Berrougui H, Cloutier M, Isabelle M, Fulop T, Payette H, Khalil A (2006) Age-related decrease in high-density lipoproteins antioxidant activity is due to an alteration in the PON1’s free sulfhydryl groups. Atherosclerosis 185:191–200

    Article  PubMed  CAS  Google Scholar 

  • Kabouridis PS (2006) Lipid rafts in T cell receptor signalling. Mol Membr Biol 23:49–57

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Katsanidis E, Addis PB (1999) Novel HPLC analysis of tocopherols, tocotrienols, and cholesterol in tissue. Free Radic Biol Med 27:1137–1140

    Article  PubMed  CAS  Google Scholar 

  • Khalil A, Berrougui H, Pawelec G, Fulop T (2012) Impairment of the ABCA1 and SR-BI-mediated cholesterol efflux pathways and HDL anti-inflammatory activity in Alzheimer’s disease. Mech Ageing Dev 133:20–29

    Article  PubMed  CAS  Google Scholar 

  • Khera AV, Cuchel M, de la Llera-Moya M, Rodrigues A, Burke MF, Jafri K, French BC, Phillips JA, Mucksavage ML, Wilensky RL, Mohler ER, Rothblat GH, Rader DJ (2011) Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis. N Engl J Med 364:127–135

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Landry YD, Denis M, Nandi S, Bell S, Vaughan AM, Zha X (2006) ATP-binding cassette transporter A1 expression disrupts raft membrane microdomains through its ATPase-related functions. J Biol Chem 281:36091–36101

    Article  PubMed  CAS  Google Scholar 

  • Larbi A, Dupuis G, Douziech N, Khalil A, Fulop T (2004a) Low-grade inflammation with aging has consequences for T-lymphocyte signaling. Ann NY Acad Sci 2004(1030):125–133

    Article  Google Scholar 

  • Larbi A, Douziech N, Dupuis G, Khalil A, Pelletier Guerard KP, Fülöp T (2004b) Age-associated alterations in the recruitment of signal-transduction proteins to lipid rafts in human T lymphocytes. J Leukoc Biol 75:373–381

    Article  PubMed  CAS  Google Scholar 

  • Larbi A, Douziech N, Khalil A, Dupuis G, Gheraïri S, Guérard KP, Fülöp T (2004c) Effects of methyl-beta-cyclodextrin on T lymphocytes lipid rafts with aging. Exp Gerontol 39:551–558

    Article  PubMed  CAS  Google Scholar 

  • Larbi A, Dupuis G, Khalil A, Douziech N, Fortin C, Fülöp T (2006a) Differential role of lipid rafts in the functions of CD4+ and CD8+ human T lymphocytes with aging. Cell Signal 18:1017–1030

    Article  PubMed  CAS  Google Scholar 

  • Larbi A, Muti E, Giacconi R, Mocchegiani E, Fülöp T (2006b) Role of lipid rafts in activation-induced cell death: the fas pathway in aging. Adv Exp Med Biol 584:137–155

    Article  PubMed  CAS  Google Scholar 

  • Larbi A, Franceschi C, Mazzatti D, Solana R, Wikby A, Pawelec G (2008) Aging of the immune system as a prognostic factor for human longevity. Physiology (Bethesda) 23:64–74

    Article  CAS  Google Scholar 

  • Larbi A, Pawelec G, Wong SC, Goldeck D, Tai JJ, Fulop T (2011) Impact of age on T cell signaling: a general defect or specific alterations? Ageing Res Rev 10:370–378

    Article  PubMed  CAS  Google Scholar 

  • Larbi A, Rymkiewicz P, Asudev A, Low I, Shadan BN, Mustafah S et al (2013) The immune system in the elderly: a fair fight against diseases. Aging Health 9:1–13

    Article  Google Scholar 

  • Le Page A, Fortin C, Garneau H, Allard N, Tsvetkova K, Tan CT, Larbi A, Dupuis G, Fülöp T (2014) Downregulation of inhibitory SRC Homology 2 Domain-containing Phosphatase-1 (SHP-1) leads to recovery of T cell responses in elderly. Cell Commun Signal 9 12(1):2

    Article  Google Scholar 

  • Lighart GH (2001) The SENIEUR protocol after 16 years: the next step is to study the interaction of ageing and disease. Mech Ageing Dev 122:136–140

    Article  Google Scholar 

  • López-Otín C, Blasco MA, Partridge L, Serrano M, Kroemer G (2013) The hallmarks of aging. Cell 153:1194–217

    Article  PubMed  PubMed Central  Google Scholar 

  • Maczek C, Bock G, Jurgens G, Schonitzer D, Dietrich H, Wick G (1998) Environmental influence on age-related changes of human lymphocyte membrane viscosity using severe combined immunodeficiency mice as an in vivo model. Exp Gerontol 33:485–498

    Article  PubMed  CAS  Google Scholar 

  • Murphy AJ, Woollard KJ, Hoang A, Mukhamedova N, Stirzaker RA, McCormick SP, Remaley AT, Sviridov D, Chin-Dusting J (2008) High-density lipoprotein reduces the human monocyte inflammatory response. Arterioscler Thromb Vasc Biol 28:2071–2077

    Article  PubMed  CAS  Google Scholar 

  • Murphy AJ, Woollard KJ, Suhartoyo A, Stirzaker RA, Shaw J, Sviridov D, Chin-Dusting JP (2011) Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation. Arterioscler Thromb Vasc Biol 31:1333–1341

    Article  PubMed  CAS  Google Scholar 

  • Norata GD, Pirillo A, Catapano AL (2011) HDLs, immunity, and atherosclerosis. Curr Opin Lipidol 22:410–416

    Article  PubMed  CAS  Google Scholar 

  • Norata GD, Pirillo A, Ammirati E, Catapano AL (2012) Emerging role of high density lipoproteins as a player in the immune system. Atherosclerosis 220:11–21

    Article  PubMed  CAS  Google Scholar 

  • Park KH, Cho KH (2011) High-density lipoprotein (HDL) from elderly and reconstituted HDL containing glycated apolipoproteins A-I share proatherosclerotic and prosenescent properties with increased cholesterol influx. J Gerontol A Biol Sci Med Sci 66:511–520

    Article  PubMed  Google Scholar 

  • Pawelec G (2012) Hallmarks of human “immunosenescence”: adaptation or dysregulation? Immun Ageing 9:15

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Perrin-Cocon L, Diaz O, Carreras M, Dollet S, Guironnet-Paquet A, André P, Lotteau V (2012) High-density lipoprotein phospholipids interfere with dendritic cell Th1 functional maturation. Immunobiology 217:91–99

    Article  PubMed  CAS  Google Scholar 

  • Rea IM, McKeown PP, McMaster D, Young IS, Patterson C, Savage MJ, Belton C, Marchegiani F, Olivieri F, Bonafe M, Franceschi C (2004) Paraoxonase polymorphisms PON1 192 and 55 and longevity in Italian centenarians and Irish nonagenarians. A pooled analysis. Exp Gerontol 39:629–35

    Article  PubMed  CAS  Google Scholar 

  • Reichardt P, Dornbach B, Gunzer M (2010) APC, T cells, and the immune synapse. Curr Top Microbiol Immunol 340:229–249

    PubMed  CAS  Google Scholar 

  • Sattler W, Mohr D, Stocker R (1994) Rapid isolation of lipoproteins and assessment of their peroxidation by high-performance liquid chromatography postcolumn chemiluminescence. Methods Enzymol 233:469–489

    Article  PubMed  CAS  Google Scholar 

  • Simons K, Gerl MJ (2010) Revitalizing membrane rafts: new tools and insights. Nature Rev Mol Cell Biol 11:688–699

    Article  CAS  Google Scholar 

  • Simons K, Sampaio JL (2011) Membrane organization and lipid rafts. Cold Spring Harb Perspect Biol 3:a004697

    Article  PubMed  PubMed Central  Google Scholar 

  • Wang SH, Yuan SG, Peng DQ, Zhao SP (2012) HDL and ApoA-I inhibit antigen presentation-mediated T cell activation by disrupting lipid rafts in antigen presenting cells. Atherosclerosis 225:105–114

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants from the Canadian Institutes of Health Research (CIHR) (No. 106634 and No. 106701), the Université de Sherbrooke, the Research Center on Aging, and the Agency for Science Technology and Research (A*STAR), Singapore. Anis Larbi is part of the ISAC Scholar program. The manuscript was edited by Neil McCarthy of Insight Editing London.

Competing interests

The authors declare that they do not have any competing interests.

Author contributions

Conceived and designed the experiments: AL, AK, GD, TF. Performed the experiments: CF, AL, HB. Analyzed the data and wrote the manuscript: TF, AL, GD, AK.

Author information

Authors and Affiliations

  1. Singapore Immunology Network (SIgN), Biopolis, Agency for Science, Technology and Research (A*STAR), Singapore, Singapore

    Anis Larbi

  2. Research Center on Aging, University of Sherbrooke, Sherbrooke, Canada

    Carl Fortin, Hicham Berrougui, Abdelouahed Khalil & Tamas Fulop

  3. Clinical Research Center, Faculty of Medicine, University of Sherbrooke, Sherbrooke, Canada

    Gilles Dupuis

Authors
  1. Anis Larbi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Carl Fortin
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Gilles Dupuis
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Hicham Berrougui
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Abdelouahed Khalil
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Tamas Fulop
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Anis Larbi or Tamas Fulop.

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Larbi, A., Fortin, C., Dupuis, G. et al. Immunomodulatory role of high-density lipoproteins: impact on immunosenescence. AGE 36, 9712 (2014). https://doi.org/10.1007/s11357-014-9712-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11357-014-9712-6

Keywords

Search

Navigation