Skip to main content

Advertisement

Log in

KLRG1—more than a marker for T cell senescence

  • Published:
AGE Aims and scope Submit manuscript

Abstract

The co-inhibitory receptor killer-cell lectin like receptor G1 (KLRG1) is expressed on NK cells and antigen-experienced T cells and has been postulated to be a marker of senescence. Whilst KLRG1 has frequently been used as a marker of cellular differentiation, data are emerging indicating that KLRG1 plays an inhibitory role. In this review we examine evidence highlighting this view of KLRG1 with emphasis on the functional defects that arise during T cell differentiation with age that may, in part, be actively maintained by inhibitory receptor signalling.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

  • Abramson J, Xu R, Pecht I (2002) An unusual inhibitory receptor-the mast cell function-associated antigen (MAFA). Mol Immunol 38:1307–1313. doi:10.1016/S0161-5890(02)00080-9

    Article  CAS  PubMed  Google Scholar 

  • Ackermann RJ, Monroe PW (1996) Bacteremic urinary tract infection in older people. J Am Geriatr Soc 44:927–933

    CAS  PubMed  Google Scholar 

  • Akbar AN, Fletcher JM (2005) Memory T cell homeostasis and senescence during aging. Curr Opin Immunol 17:480–485. doi:10.1016/j.coi.2005.07.019

    Article  CAS  PubMed  Google Scholar 

  • Akbar AN, Terry L, Timms A, Beverley PC, Janossy G (1988) Loss of CD45R and gain of UCHL1 reactivity is a feature of primed T cells. J Immunol 140:2171–2178

    CAS  PubMed  Google Scholar 

  • Alessi DR, Andjelkovic M, Caudwell B, Cron P, Morrice N, Cohen P, Hemmings BA (1996) Mechanism of activation of protein kinase B by insulin and IGF-1. EMBO J 15:6541–6551

    CAS  PubMed  Google Scholar 

  • Amyes E, Hatton C, Montamat-Sicotte D, Gudgeon N, Rickinson AB, McMichael AJ, Callan MF (2003) Characterization of the CD4+ T cell response to Epstein-Barr virus during primary and persistent infection. J Exp Med 198:903–911. doi:10.1084/jem.20022058

    Article  CAS  PubMed  Google Scholar 

  • Appay V, Dunbar PR, Callan M, Klenerman P, Gillespie GM, Papagno L, Ogg GS, King A, Lechner F, Spina CA, Little S, Havlir DV, Richman DD, Gruener N, Pape G, Waters A, Easterbrook P, Salio M, Cerundolo V, McMichael AJ, Rowland-Jones SL (2002) Memory CD8+ T cells vary in differentiation phenotype in different persistent virus infections. Nat Med 8:379–385. doi:10.1038/nm0402-379

    Article  CAS  PubMed  Google Scholar 

  • Appay V, Almeida JR, Sauce D, Autran B, Papagno L (2007) Accelerated immune senescence and HIV-1 infection. Exp Gerontol 42:432–437. doi:10.1016/j.exger.2006.12.003

    Article  CAS  PubMed  Google Scholar 

  • Barker WH, Mullooly JP (1980) Impact of epidemic type A influenza in a defined adult population. Am J Epidemiol 112:798–811

    CAS  PubMed  Google Scholar 

  • Beyersdorf NB, Ding X, Karp K, Hanke T (2001) Expression of inhibitory "killer cell lectin-like receptor G1" identifies unique subpopulations of effector and memory CD8 T cells. Eur J Immunol 31:3443–3452. doi:10.1002/1521-4141(200112)31:12<3443::AID-IMMU3443>3.0.CO;2-J

    Article  CAS  PubMed  Google Scholar 

  • Blaser C, Kaufmann M, Pircher H (1998) Virus-activated CD8 T cells and lymphokine-activated NK cells express the mast cell function-associated antigen, an inhibitory C-type lectin. J Immunol 161:6451–6454

    CAS  PubMed  Google Scholar 

  • Bukczynski J, Wen T, Watts TH (2003) Costimulation of human CD28- T cells by 4-1BB ligand. Eur J Immunol 33:446–454. doi:10.1002/immu.200310020

    Article  CAS  PubMed  Google Scholar 

  • Champagne P, Ogg GS, King AS, Knabenhans C, Ellefsen K, Nobile M, Appay V, Rizzardi GP, Fleury S, Lipp M, Forster R, Rowland-Jones S, Sekaly RP, McMichael AJ, Pantaleo G (2001) Skewed maturation of memory HIV-specific CD8 T lymphocytes. Nature 410:106–111. doi:10.1038/35065118

    Article  CAS  PubMed  Google Scholar 

  • Chattopadhyay B, Al-Zahawi M (1983) Septicaemia and its unacceptably high mortality in the elderly. J Infect 7:134–138. doi:10.1016/S0163-4453(83)90548-0

    Article  CAS  PubMed  Google Scholar 

  • 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. doi:10.1016/j.clim.2007.12.002

    Article  CAS  PubMed  Google Scholar 

  • Donahue AC, Fruman DA (2004) PI3K signaling controls cell fate at many points in B lymphocyte development and activation. Semin Cell Dev Biol 15:183–197. doi:10.1016/j.semcdb.2003.12.024

    Article  CAS  PubMed  Google Scholar 

  • Douek DC, McFarland RD, Keiser PH, Gage EA, Massey JM, Haynes BF, Polis MA, Haase AT, Feinberg MB, Sullivan JL, Jamieson BD, Zack JA, Picker LJ, Koup RA (1998) Changes in thymic function with age and during the treatment of HIV infection. Nature 396:690–695. doi:10.1038/25374

    Article  CAS  PubMed  Google Scholar 

  • Eberl M, Engel R, Aberle S, Fisch P, Jomaa H, Pircher H (2005) Human Vgamma9/Vdelta2 effector memory T cells express the killer cell lectin-like receptor G1 (KLRG1). J Leukoc Biol 77:67–70

    CAS  PubMed  Google Scholar 

  • Effros RB, Boucher N, Porter V, Zhu X, Spaulding C, Walford RL, Kronenberg M, Cohen D, Schachter F (1994) Decline in CD28+ T cells in centenarians and in long-term T cell cultures: a possible cause for both in vivo and in vitro immunosenescence. Exp Gerontol 29:601–609. doi:10.1016/0531-5565(94)90073-6

    Article  CAS  PubMed  Google Scholar 

  • Effros RB, Dagarag M, Spaulding C, Man J (2005) The role of CD8+ T-cell replicative senescence in human aging. Immunol Rev 205:147–157. doi:10.1111/j.0105-2896.2005.00259.x

    Article  CAS  PubMed  Google Scholar 

  • Faint JM, Annels NE, Curnow SJ, Shields P, Pilling D, Hislop AD, Wu L, Akbar AN, Buckley CD, Moss PA, Adams DH, Rickinson AB, Salmon M (2001) Memory T cells constitute a subset of the human CD8+CD45RA+pool with distinct phenotypic and migratory characteristics. J Immunol 167:212–220

    CAS  PubMed  Google Scholar 

  • Fletcher JM, Vukmanovic-Stejic M, Dunne PJ, Birch KE, Cook JE, Jackson SE, Salmon M, Rustin MH, Akbar AN (2005) Cytomegalovirus-specific CD4+ T cells in healthy carriers are continuously driven to replicative exhaustion. J Immunol 175:8218–8225

    CAS  PubMed  Google Scholar 

  • Goronzy JJ, Fulbright JW, Crowson CS, Poland GA, O'Fallon WM, Weyand CM (2001) Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J Virol 75:12182–12187. doi:10.1128/JVI.75.24.12182-12187.2001

    Article  CAS  PubMed  Google Scholar 

  • Goronzy JJ, Lee WW, Weyand CM (2007) Aging and T-cell diversity. Exp Gerontol 42:400–406. doi:10.1016/j.exger.2006.11.016

    Article  CAS  PubMed  Google Scholar 

  • Gorse GJ, Thrupp LD, Nudleman KL, Wyle FA, Hawkins B, Cesario TC (1984) Bacterial meningitis in the elderly. Arch Intern Med 144:1603–1607. doi:10.1001/archinte.144.8.1603

    Article  CAS  PubMed  Google Scholar 

  • Grundemann C, Bauer M, Schweier O, von Oppen N, Lassing U, Saudan P, Becker KF, Karp K, Hanke T, Bachmann MF, Pircher H (2006) Cutting edge: identification of E-cadherin as a ligand for the murine killer cell lectin-like receptor G1. J Immunol 176:1311–1315

    PubMed  Google Scholar 

  • Gumbiner BM (2005) Regulation of cadherin-mediated adhesion in morphogenesis. Nat Rev Mol Cell Biol 6:622–634. doi:10.1038/nrm1699

    Article  CAS  PubMed  Google Scholar 

  • Hamann D, Baars PA, Rep MH, Hooibrink B, Kerkhof-Garde SR, Klein MR, van Lier RA (1997) Phenotypic and functional separation of memory and effector human CD8+ T cells. J Exp Med 186:1407–1418. doi:10.1084/jem.186.9.1407

    Article  CAS  PubMed  Google Scholar 

  • Hanke T, Corral L, Vance RE, Raulet DH (1998) 2F1 antigen, the mouse homolog of the rat "mast cell function-associated antigen", is a lectin-like type II transmembrane receptor expressed by natural killer cells. Eur J Immunol 28:4409–4417. doi:10.1002/(SICI)1521-4141(199812) 28:12<4409::AID-IMMU4409>3.0.CO;2-3

    Article  CAS  PubMed  Google Scholar 

  • Hayward AR, Buda K, Levin MJ (1994) Immune response to secondary immunization with live or inactivated VZV vaccine in elderly adults. Viral Immunol 7:31–36. doi:10.1089/vim.1994.7.31

    Article  CAS  PubMed  Google Scholar 

  • Henson SM, Franzese O, Macaulay R, Libri V, Azevedo RI, Kiani-Alikhan S, Plunkett FJ, Masters JE, Jackson S, Griffiths S, Pircher HP, Soares MV, Akbar AN (2009) KLRG1 signaling induces defective Akt (Ser473) phosphorylation and proliferative dysfunction of highly differentiated CD8+ T cells. Blood (Apr):30. Epub ahead of print

  • Ito M, Maruyama T, Saito N, Koganei S, Yamamoto K, Matsumoto N (2006) Killer cell lectin-like receptor G1 binds three members of the classical cadherin family to inhibit NK cell cytotoxicity. J Exp Med 203:289–295. doi:10.1084/jem.20051986

    Article  PubMed  Google Scholar 

  • Jacinto E, Facchinetti V, Liu D, Soto N, Wei S, Jung SY, Huang Q, Qin J, Su B (2006) SIN1/MIP1 maintains rictor-mTOR complex integrity and regulates Akt phosphorylation and substrate specificity. Cell 127:125–137. doi:10.1016/j.cell.2006.08.033

    Article  CAS  PubMed  Google Scholar 

  • Joshi NS, Cui W, Chandele A, Lee HK, Urso DR, Hagman J, Gapin L, Kaech SM (2007) Inflammation directs memory precursor and short-lived effector CD8(+) T cell fates via the graded expression of T-bet transcription factor. Immunity 27:281–295. doi:10.1016/j.immuni.2007.07.010

    Article  CAS  PubMed  Google Scholar 

  • Koch S, Larbi A, Dehovanessian E, Ozcelik D, Naumova E, Pawelec G (2008) Multiparameter flow cytometric analysis of CD4 and CD8 T cell subsets in young and old people. Immun Ageing 5:6. doi:10.1186/1742-4933-5-6

    Article  PubMed  Google Scholar 

  • LaCroix AZ, Lipson S, Miles TP, White L (1989) Prospective study of pneumonia hospitalizations and mortality of U.S. older people: the role of chronic conditions, health behaviors, and nutritional status. Public Health Rep 104:350–360

    CAS  PubMed  Google Scholar 

  • Linton PJ, Dorshkind K (2004) Age-related changes in lymphocyte development and function. Nat Immunol 5:133–139. doi:10.1038/ni1033

    Article  CAS  PubMed  Google Scholar 

  • Marcolino I, Przybylski GK, Koschella M, Schmidt CA, Voehringer D, Schlesier M, Pircher H (2004) Frequent expression of the natural killer cell receptor KLRG1 in human cord blood T cells: correlation with replicative history. Eur J Immunol 34:2672–2680. doi:10.1002/eji.200425282

    Article  CAS  PubMed  Google Scholar 

  • Messaoudi I, Lemaoult J, Guevara-Patino JA, Metzner BM, Nikolich-Zugich J (2004) Age-related CD8 T cell clonal expansions constrict CD8 T cell repertoire and have the potential to impair immune defense. J Exp Med 200:1347–1358. doi:10.1084/jem.20040437

    Article  CAS  PubMed  Google Scholar 

  • Mousavi SF, Soroosh P, Takahashi T, Yoshikai Y, Shen H, Lefrancois L, Borst J, Sugamura K, Ishii N (2008) OX40 costimulatory signals potentiate the memory commitment of effector CD8+ T cells. J Immunol 181:5990–6001

    CAS  PubMed  Google Scholar 

  • Ouyang Q, Wagner WM, Voehringer D, Wikby A, Klatt T, Walter S, Muller CA, Pircher H, Pawelec G (2003) Age-associated accumulation of CMV-specific CD8+ T cells expressing the inhibitory killer cell lectin-like receptor G1 (KLRG1). Exp Gerontol 38:911–920. doi:10.1016/S0531-5565(03)00134-7

    Article  CAS  PubMed  Google Scholar 

  • Pawelec G, Akbar AN, Caruso C, Effros R, Grubeck-Loebenstein B, Wikby A (2004) Is immunosenescence infectious? Trends Immunol 25:406–410. doi:10.1016/j.it.2004.05.006

    Article  CAS  PubMed  Google Scholar 

  • Plunkett FJ, Franzese O, Belaramani LL, Fletcher JM, Gilmour KC, Sharifi R, Khan N, Hislop AD, Cara A, Salmon M, Gaspar HB, Rustin MH, Webster D, Akbar AN (2005) The impact of telomere erosion on memory CD8+ T cells in patients with X-linked lymphoproliferative syndrome. Mech Ageing Dev 126:855–865. doi:10.1016/j.mad.2005.03.006

    Article  CAS  PubMed  Google Scholar 

  • Plunkett FJ, Franzese O, Finney HM, Fletcher JM, Belaramani LL, Salmon M, Dokal I, Webster D, Lawson AD, Akbar AN (2007) The loss of telomerase activity in highly differentiated CD8+CD28-CD27- T cells is associated with decreased Akt (Ser473) phosphorylation. J Immunol 178:7710–7719

    CAS  PubMed  Google Scholar 

  • Robbins SH, Nguyen KB, Takahashi N, Mikayama T, Biron CA, Brossay L (2002) Cutting edge: inhibitory functions of the killer cell lectin-like receptor G1 molecule during the activation of mouse NK cells. J Immunol 168:2585–2589

    CAS  PubMed  Google Scholar 

  • Rosshart S, Hofmann M, Schweier O, Pfaff AK, Yoshimoto K, Takeuchi T, Molnar E, Schamel WW, Pircher H (2008) Interaction of KLRG1 with E-cadherin: new functional and structural insights. Eur J Immunol 38:3354–3364. doi:10.1002/eji.200838690

    Article  CAS  PubMed  Google Scholar 

  • Sallusto F, Geginat J, Lanzavecchia A (2004) Central memory and effector memory T cell subsets: function, generation, and maintenance. Annu Rev Immunol 22:745–763. doi:10.1146/annurev.immunol.22.012703.104702

    Article  CAS  PubMed  Google Scholar 

  • Schwartzkopff S, Grundemann C, Schweier O, Rosshart S, Karjalainen KE, Becker KF, Pircher H (2007) Tumor-associated E-cadherin mutations affect binding to the killer cell lectin-like receptor G1 in humans. J Immunol 179:1022–1029

    CAS  PubMed  Google Scholar 

  • Serghides L, Bukczynski J, Wen T, Wang C, Routy JP, Boulassel MR, Sekaly RP, Ostrowski M, Bernard NF, Watts TH (2005) Evaluation of OX40 ligand as a costimulator of human antiviral memory CD8 T cell responses: comparison with B7.1 and 4-1BBL. J Immunol 175:6368–6377

    CAS  PubMed  Google Scholar 

  • Sprenger MJ, Mulder PG, Beyer WE, Van Strik R, Masurel N (1993) Impact of influenza on mortality in relation to age and underlying disease, 1967–1989. Int J Epidemiol 22:334–340. doi:10.1093/ije/22.2.334

    Article  CAS  PubMed  Google Scholar 

  • Stepanova L, Naykhin A, Kolmskog C, Jonson G, Barantceva I, Bichurina M, Kubar O, Linde A (2002) The humoral response to live and inactivated influenza vaccines administered alone and in combination to young adults and elderly. J Clin Virol 24:193–201. doi:10.1016/S1386-6532(01)00246-3

    Article  CAS  PubMed  Google Scholar 

  • Tessmer MS, Fugere C, Stevenaert F, Naidenko OV, Chong HJ, Leclercq G, Brossay L (2007) KLRG1 binds cadherins and preferentially associates with SHIP-1. Int Immunol 19:391–400. doi:10.1093/intimm/dxm004

    Article  CAS  PubMed  Google Scholar 

  • Thimme R, Appay V, Koschella M, Panther E, Roth E, Hislop AD, Rickinson AB, Rowland-Jones SL, Blum HE, Pircher H (2005) Increased expression of the NK cell receptor KLRG1 by virus-specific CD8 T cells during persistent antigen stimulation. J Virol 79:12112–12116. doi:10.1128/JVI.79.18.12112-12116.2005

    Article  CAS  PubMed  Google Scholar 

  • Voehringer D, Blaser C, Brawand P, Raulet DH, Hanke T, Pircher H (2001) Viral infections induce abundant numbers of senescent CD8 T cells. J Immunol 167:4838–4843

    CAS  PubMed  Google Scholar 

  • Voehringer D, Koschella M, Pircher H (2002) Lack of proliferative capacity of human effector and memory T cells expressing killer cell lectinlike receptor G1 (KLRG1). Blood 100:3698–3702. doi:10.1182/blood-2002-02-0657

    Article  CAS  PubMed  Google Scholar 

  • Waller EC, McKinney N, Hicks R, Carmichael AJ, Sissons JG, Wills MR (2007) Differential costimulation through CD137 (4-1BB) restores proliferation of human virus-specific "effector memory" (CD28(-) CD45RA(HI)) CD8(+) T cells. Blood 110:4360–4366. doi:10.1182/blood-2007-07-104604

    Article  CAS  PubMed  Google Scholar 

  • Wick G, Jansen-Durr P, Berger P, Blasko I, Grubeck-Loebenstein B (2000) Diseases of aging. Vaccine 18:1567–1583. doi:10.1016/S0264-410X(99)00489-2

    Article  CAS  PubMed  Google Scholar 

  • Xu R, Abramson J, Fridkin M, Pecht I (2001) SH2 domain-containing inositol polyphosphate 5′-phosphatase is the main mediator of the inhibitory action of the mast cell function-associated antigen. J Immunol 167:6394–6402

    CAS  PubMed  Google Scholar 

  • Yoshikawa TT (1997) Perspective: aging and infectious diseases: past, present, and future. J Infect Dis 176:1053–1057. doi:10.1086/516547

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by a Research into Ageing Fellowship to S.M.H. and funding from the British Biotechnology and Biological Research Council to A.N.A.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Sian M. Henson.

About this article

Cite this article

Henson, S.M., Akbar, A.N. KLRG1—more than a marker for T cell senescence. AGE 31, 285–291 (2009). https://doi.org/10.1007/s11357-009-9100-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11357-009-9100-9

Keywords

Navigation