Advertisement

Changes in Natural Killer Cells in Aged Mice

  • Savita Nair
  • Luis J. SigalEmail author
Living reference work entry

Abstract

Immune dysfunctions in the elderly result in increased susceptibility to infectious diseases, cancer, or autoimmune diseases. Natural killer (NK) cells are bone marrow derived lymphocytes crucial for host defense against several infections and cancer. It is known that aged C57BL/6 mice compared to young mice have decreased numbers of mature NK cells in the blood, spleen, and bone marrow, resulting in susceptibility to mousepox, a lethal disease caused by Ectromelia virus. The chapter discusses newly described age-related defects in NK cells including reduced proliferation in vivo, dysregulated expression of activating and inhibitory receptors, and altered expression of collagen binding integrins. The chapter also describes that the defect in NK maturation is the consequence of deficient maturational cues provided by bone marrow stromal cells. Treatment with complexes of the cytokine IL-15 and IL-15Rα induce massive expansion of the NK cells but most of these NK cells remain immature and are unable to restore resistance to mousepox. Therefore, it may be crucial to design therapies that specifically increase mature NK cell numbers in the aged.

Keywords

Aging Natural killer cells Immunosenescence Cellular immunology Immune cell development Mice NK cell development and maturation Bone marrow Stromal cell defect Integrins 

References

  1. Albright JW, Albright JF (1983) Age-associated impairment of murine natural killer activity. Proc Natl Acad Sci USA 80(20):6371–6375PubMedCrossRefGoogle Scholar
  2. Arase H, Saito T, Phillips JH, Lanier LL (2001) Cutting edge: the mouse NK cell-associated antigen recognized by DX5 monoclonal antibody is CD49b (alpha 2 integrin, very late antigen-2). J Immunol 167(3):1141–1144PubMedCrossRefGoogle Scholar
  3. Beli E, Duriancik DM, Clinthorne JF, Lee T, Kim S, Gardner EM (2013) Natural killer cell development and maturation in aged mice. Mech Ageing Dev 135:33PubMedPubMedCentralCrossRefGoogle Scholar
  4. Bernardini G, Sciume G, Bosisio D, Morrone S, Sozzani S, Santoni A (2008) CCL3 and CXCL12 regulate trafficking of mouse bone marrow NK cell subsets. Blood 111(7):3626–3634PubMedCrossRefGoogle Scholar
  5. Bukowski JF, Woda BA, Welsh RM (1984) Pathogenesis of murine cytomegalovirus infection in natural killer cell-depleted mice. J Virol 52(1):119–128PubMedPubMedCentralGoogle Scholar
  6. Carlyle JR, Mesci A, Ljutic B, Belanger S, Tai LH, Rousselle E, Troke AD, Proteau MF, Makrigiannis AP (2006) Molecular and genetic basis for strain-dependent NK1.1 alloreactivity of mouse NK cells. J Immunol 176(12):7511–7524PubMedCrossRefGoogle Scholar
  7. Chinn IK, Blackburn CC, Manley NR, Sempowski GD (2012) Changes in primary lymphoid organs with aging. Semin Immunol 24(5):309–320PubMedPubMedCentralCrossRefGoogle Scholar
  8. Chiu BC, Martin BE, Stolberg VR, Chensue SW (2013) The host environment is responsible for aging-related functional NK cell deficiency. J Immunol 191(9):4688–4698PubMedCrossRefGoogle Scholar
  9. Colucci F, Caligiuri MA, Di Santo JP (2003) What does it take to make a natural killer? Nat Rev Immunol 3(5):413–425PubMedCrossRefGoogle Scholar
  10. Coombes JL, Han SJ, van Rooijen N, Raulet DH, Robey EA (2012) Infection-induced regulation of natural killer cells by macrophages and collagen at the lymph node subcapsular sinus. Cell Rep 2(1):124–135PubMedPubMedCentralCrossRefGoogle Scholar
  11. Cui G, Hara T, Simmons S, Wagatsuma K, Abe A, Miyachi H, Kitano S, Ishii M, Tani-ichi S, Ikuta K (2014) Characterization of the IL-15 niche in primary and secondary lymphoid organs in vivo. Proc Natl Acad Sci USA 111(5):1915–1920PubMedCrossRefGoogle Scholar
  12. Daussy C, Faure F, Mayol K, Viel S, Gasteiger G, Charrier E, Bienvenu J, Henry T, Debien E, Hasan UA, Marvel J, Yoh K, Takahashi S, Prinz I, de Bernard S, Buffat L, Walzer T (2014) T-bet and Eomes instruct the development of two distinct natural killer cell lineages in the liver and in the bone marrow. J Exp Med 211(3):563–577PubMedPubMedCentralCrossRefGoogle Scholar
  13. Delano ML, Brownstein DG (1995) Innate resistance to lethal mousepox is genetically linked to the NK gene complex on chromosome 6 and correlates with early restriction of virus replication by cells with an NK phenotype. J Virol 69(9):5875–5877PubMedPubMedCentralGoogle Scholar
  14. Dorshkind K, Montecino-Rodriguez E, Signer RA (2009) The ageing immune system: is it ever too old to become young again? Nat Rev Immunol 9(1):57–62PubMedCrossRefGoogle Scholar
  15. Dubois S, Patel HJ, Zhang M, Waldmann TA, Muller JR (2008) Preassociation of IL-15 with IL-15R alpha-IgG1-Fc enhances its activity on proliferation of NK and CD8+/CD44high T cells and its antitumor action. J Immunol 180(4):2099–2106PubMedCrossRefGoogle Scholar
  16. Elpek KG, Rubinstein MP, Bellemare-Pelletier A, Goldrath AW, Turley SJ (2010) Mature natural killer cells with phenotypic and functional alterations accumulate upon sustained stimulation with IL-15/IL-15Ralpha complexes. Proc Natl Acad Sci USA 107(50):21647–21652PubMedCrossRefGoogle Scholar
  17. Esteban DJ, Buller RM (2005) Ectromelia virus: the causative agent of mousepox. J Gen Virol 86(Pt 10):2645–2659PubMedCrossRefGoogle Scholar
  18. Fang M, Lanier LL, Sigal LJ (2008) A role for NKG2D in NK cell-mediated resistance to poxvirus disease. PLoS Pathog 4(2):e30PubMedPubMedCentralCrossRefGoogle Scholar
  19. Fang M, Roscoe F, Sigal LJ (2010) Age-dependent susceptibility to a viral disease due to decreased natural killer cell numbers and trafficking. J Exp Med 207(11):2369–2381PubMedPubMedCentralCrossRefGoogle Scholar
  20. Fang M, Orr MT, Spee P, Egebjerg T, Lanier LL, Sigal LJ (2011) CD94 is essential for NK cell-mediated resistance to a lethal viral disease. Immunity 34(4):579–589PubMedPubMedCentralCrossRefGoogle Scholar
  21. Feng CG, Kaviratne M, Rothfuchs AG, Cheever A, Hieny S, Young HA, Wynn TA, Sher A (2006) NK cell-derived IFN-gamma differentially regulates innate resistance and neutrophil response in T cell-deficient hosts infected with Mycobacterium tuberculosis. J Immunol 177(10):7086–7093PubMedCrossRefGoogle Scholar
  22. Flint SJ (2009) Principles of virology. ASM Press, Washington, DCGoogle Scholar
  23. Giorda R, Weisberg EP, Ip TK, Trucco M (1992) Genomic structure and strain-specific expression of the natural killer cell receptor NKR-P1. J Immunol 149(6):1957–1963PubMedGoogle Scholar
  24. Gordon SM, Chaix J, Rupp LJ, Wu J, Madera S, Sun JC, Lindsten T, Reiner SL (2010) The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36(1):55–67CrossRefGoogle Scholar
  25. Hayakawa Y, Smyth MJ (2006) CD27 dissects mature NK cells into two subsets with distinct responsiveness and migratory capacity. J Immunol 176(3):1517–1524PubMedCrossRefGoogle Scholar
  26. Hazeldine J, Hampson P, Lord JM (2012) Reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity. Aging Cell 11(5):751–759PubMedCrossRefGoogle Scholar
  27. Hood JD, Cheresh DA (2002) Role of integrins in cell invasion and migration. Nat Rev Cancer 2(2):91–100PubMedCrossRefGoogle Scholar
  28. Huntington ND, Tabarias H, Fairfax K, Brady J, Hayakawa Y, Degli-Esposti MA, Smyth MJ, Tarlinton DM, Nutt SL (2007) NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J Immunol 178(8):4764–4770PubMedCrossRefGoogle Scholar
  29. Kennedy MK, Glaccum M, Brown SN, Butz EA, Viney JL, Embers M, Matsuki N, Charrier K, Sedger L, Willis CR, Brasel K, Morrissey PJ, Stocking K, Schuh JC, Joyce S, Peschon JJ (2000) Reversible defects in natural killer and memory CD8 T cell lineages in interleukin 15-deficient mice. J Exp Med 191(5):771–780PubMedPubMedCentralCrossRefGoogle Scholar
  30. Kim S, Iizuka K, Kang HS, Dokun A, French AR, Greco S, Yokoyama WM (2002) In vivo developmental stages in murine natural killer cell maturation. Nat Immunol 3(6):523–528PubMedCrossRefGoogle Scholar
  31. Labrie JE 3rd, Borghesi L, Gerstein RM (2005) Bone marrow microenvironmental changes in aged mice compromise V(D)J recombinase activity and B cell generation. Semin Immunol 17(5):347–355PubMedCrossRefGoogle Scholar
  32. Lang PO, Mendes A, Socquet J, Assir N, Govind S, Aspinall R (2012) Effectiveness of influenza vaccine in aging and older adults: comprehensive analysis of the evidence. Clin Interv Aging 7:55–64PubMedPubMedCentralCrossRefGoogle Scholar
  33. Lanier LL (2008) Up on the tightrope: natural killer cell activation and inhibition. Nat Immunol 9(5):495–502PubMedPubMedCentralCrossRefGoogle Scholar
  34. Leitinger B, Hohenester E (2007) Mammalian collagen receptors. Matrix Biol 26(3):146–155PubMedCrossRefGoogle Scholar
  35. Leng J, Goldstein DR (2010) Impact of aging on viral infections. Microbes Infect 12(14–15):1120–1124PubMedPubMedCentralCrossRefGoogle Scholar
  36. Lodolce JP, Boone DL, Chai S, Swain RE, Dassopoulos T, Trettin S, Ma A (1998) IL-15 receptor maintains lymphoid homeostasis by supporting lymphocyte homing and proliferation. Immunity 9(5):669–676PubMedCrossRefGoogle Scholar
  37. Loh J, Chu DT, O’Guin AK, Yokoyama WM, Virgin HW (2005) Natural killer cells utilize both perforin and gamma interferon to regulate murine cytomegalovirus infection in the spleen and liver. J Virol 79(1):661–667PubMedPubMedCentralCrossRefGoogle Scholar
  38. Marcais A, Viel S, Grau M, Henry T, Marvel J, Walzer T (2013) Regulation of mouse NK cell development and function by cytokines. Front Immunol 4:450PubMedPubMedCentralCrossRefGoogle Scholar
  39. Marquardt N, Wilk E, Pokoyski C, Schmidt RE, Jacobs R (2010) Murine CXCR3+CD27bright NK cells resemble the human CD56bright NK-cell population. Eur J Immunol 40(5):1428–1439PubMedCrossRefGoogle Scholar
  40. Nair S, Fang M, Sigal LJ (2015) The natural killer cell dysfunction of aged mice is due to the bone marrow stroma and is not restored by IL-15/IL-15Ralpha treatment. Aging Cell 14(2):180–190PubMedCrossRefGoogle Scholar
  41. Nguyen N, Holodniy M (2008) HIV infection in the elderly. Clin Interv Aging 3(3):453–472PubMedPubMedCentralGoogle Scholar
  42. Nikolich-Zugich J, Li G, Uhrlaub JL, Renkema KR, Smithey MJ (2012) Age-related changes in CD8 T cell homeostasis and immunity to infection. Semin Immunol 24(5):356–364PubMedPubMedCentralCrossRefGoogle Scholar
  43. Nogusa S, Ritz BW, Kassim SH, Jennings SR, Gardner EM (2008) Characterization of age-related changes in natural killer cells during primary influenza infection in mice. Mech Ageing Dev 129(4):223–230PubMedCrossRefGoogle Scholar
  44. Nykvist P, Tu H, Ivaska J, Kapyla J, Pihlajaniemi T, Heino J (2000) Distinct recognition of collagen subtypes by alpha(1)beta(1) and alpha(2)beta(1) integrins. Alpha(1)beta(1) mediates cell adhesion to type XIII collagen. J Biol Chem 275(11):8255–8261PubMedCrossRefGoogle Scholar
  45. Orange JS (2002) Human natural killer cell deficiencies and susceptibility to infection. Microbes Infect 4(15):1545–1558PubMedCrossRefGoogle Scholar
  46. Peng H, Jiang X, Chen Y, Sojka DK, Wei H, Gao X, Sun R, Yokoyama WM, Tian Z (2013) Liver-resident NK cells confer adaptive immunity in skin-contact inflammation. J Clin Invest 123(4):1444–1456PubMedPubMedCentralCrossRefGoogle Scholar
  47. Rubinstein MP, Kovar M, Purton JF, Cho JH, Boyman O, Surh CD, Sprent J (2006) Converting IL-15 to a superagonist by binding to soluble IL-15R{alpha}. Proc Natl Acad Sci USA 103(24):9166–9171PubMedCrossRefGoogle Scholar
  48. Seidel UJ, Schlegel P, Lang P (2013) Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. Front Immunol 4:76PubMedPubMedCentralCrossRefGoogle Scholar
  49. Sojka DK, Plougastel-Douglas B, Yang L, Pak-Wittel MA, Artyomov MN, Ivanova Y, Zhong C, Chase JM, Rothman PB, Yu J, Riley JK, Zhu J, Tian Z, Yokoyama WM (2014) Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. elife 3:e01659PubMedPubMedCentralCrossRefGoogle Scholar
  50. Solana R, Tarazona R, Gayoso I, Lesur O, Dupuis G, Fulop T (2012) Innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans. Semin Immunol 24(5):331–341PubMedCrossRefGoogle Scholar
  51. Stoklasek TA, Schluns KS, Lefrancois L (2006) Combined IL-15/IL-15Ralpha immunotherapy maximizes IL-15 activity in vivo. J Immunol 177(9):6072–6080PubMedPubMedCentralCrossRefGoogle Scholar
  52. Sun JC, Lanier LL (2011) NK cell development, homeostasis and function: parallels with CD8(+) T cells. Nat Rev Immunol 11(10):645–657PubMedPubMedCentralCrossRefGoogle Scholar
  53. Vance RE, Jamieson AM, Raulet DH (1999) Recognition of the class Ib molecule Qa-1(b) by putative activating receptors CD94/NKG2C and CD94/NKG2E on mouse natural killer cells. J Exp Med 190(12):1801–1812PubMedPubMedCentralCrossRefGoogle Scholar
  54. Waterhouse EJ, Quesenberry PJ, Balian G (1986) Collagen synthesis by murine bone marrow cell culture. J Cell Physiol 127(3):397–402PubMedCrossRefGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Immuno-Oncology Infection & Immunity Translational Research Science Communications Competitive IntelligencePhiliadelphiaUSA
  2. 2.Department of Microbiology and ImmunologyThomas Jefferson UniversityPhiladelphiaUSA

Personalised recommendations