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Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity

Nature Medicine volume 18, pages 1518–1524 (2012)Cite this article

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Abstract

The ability of the human immune system to respond to vaccination declines with age. We identified an age-associated defect in T cell receptor (TCR)-induced extracellular signal–regulated kinase (ERK) phosphorylation in naive CD4+ T cells, whereas other signals, such as ζ chain–associated protein kinase 70 (ZAP70) and phospholipase C-γ1 phosphorylation, were not impaired. The defective ERK signaling was caused by the dual specific phosphatase 6 (DUSP6), whose protein expression increased with age due to a decline in repression by miR-181a. Reconstitution of miR-181a lowered DUSP6 expression in naive CD4+ T cells in elderly individuals. DUSP6 repression using miR-181a or specific siRNA and DUSP6 inhibition by the allosteric inhibitor (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one improved CD4+ T cell responses, as seen by increased expression of activation markers, improved proliferation and supported preferential T helper type 1 cell differentiation. DUSP6 is a potential intervention target for restoring T cell responses in the elderly, which may augment the effectiveness of vaccination.

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Figure 1: Decreased sensitivity of naive CD4+ T cells to respond to antigenic stimulation with age.
Figure 2: Age-associated expression of DUSP6.
Figure 3: Age-associated expression of miR-181a.
Figure 4: miR-181a controls DUSP6 expression.
Figure 5: miR-181a overexpression restores T cell activities in elderly CD4+ T cells.
Figure 6: DUSP6 inhibition augments activation of elderly CD4+ T cells.

References

  1. Weng, N.P. Aging of the immune system: how much can the adaptive immune system adapt? Immunity 24, 495–499 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Hakim, F.T. & Gress, R.E. Immunosenescence: deficits in adaptive immunity in the elderly. Tissue Antigens 70, 179–189 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Thompson, W.W. et al. Mortality associated with influenza and respiratory syncytial virus in the United States. J. Am. Med. Assoc. 289, 179–186 (2003).

    Article  Google Scholar 

  4. Targonski, P.V., Jacobson, R.M. & Poland, G.A. Immunosenescence: role and measurement in influenza vaccine response among the elderly. Vaccine 25, 3066–3069 (2007).

    Article  CAS  PubMed  Google Scholar 

  5. Nichol, K.L., Nordin, J.D., Nelson, D.B., Mullooly, J.P. & Hak, E. Effectiveness of influenza vaccine in the community-dwelling elderly. N. Engl. J. Med. 357, 1373–1381 (2007).

    Article  CAS  PubMed  Google Scholar 

  6. Nikolich-Zugich, J., Slifka, M.K. & Messaoudi, I. The many important facets of T-cell repertoire diversity. Nat. Rev. Immunol. 4, 123–132 (2004).

    Article  CAS  PubMed  Google Scholar 

  7. Haynes, B.F., Markert, M.L., Sempowski, G.D., Patel, D.D. & Hale, L.P. The role of the thymus in immune reconstitution in aging, bone marrow transplantation, and HIV-1 infection. Annu. Rev. Immunol. 18, 529–560 (2000).

    Article  CAS  PubMed  Google Scholar 

  8. Sauce, D. et al. Evidence of premature immune aging in patients thymectomized during early childhood. J. Clin. Invest. 119, 3070–3078 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Czesnikiewicz-Guzik, M. et al. T cell subset–specific susceptibility to aging. Clin. Immunol. 127, 107–118 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Naylor, K. et al. The influence of age on T cell generation and TCR diversity. J. Immunol. 174, 7446–7452 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Goronzy, J.J. & Weyand, C.M. T cell development and receptor diversity during aging. Curr. Opin. Immunol. 17, 468–475 (2005).

    Article  CAS  PubMed  Google Scholar 

  12. Tsukamoto, H. et al. Age-associated increase in lifespan of naive CD4 T cells contributes to T-cell homeostasis but facilitates development of functional defects. Proc. Natl. Acad. Sci. USA 106, 18333–18338 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Macallan, D.C. et al. Rapid turnover of effector-memory CD4+ T cells in healthy humans. J. Exp. Med. 200, 255–260 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Hodes, R.J., Hathcock, K.S. & Weng, N.P. Telomeres in T and B cells. Nat. Rev. Immunol. 2, 699–706 (2002).

    Article  CAS  PubMed  Google Scholar 

  15. Weng, N.P., Akbar, A.N. & Goronzy, J. CD28− T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Goronzy, J.J., Li, G., Yu, M. & Weyand, C.M. Signaling pathways in aged T cell—A reflection of T cell differentiation, cell senescence and host environment. Semin. Immunol. (in the press) (2012).

  17. Berg, L.J. Strength of T cell receptor signaling strikes again. Immunity 31, 529–531 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Altan-Bonnet, G. & Germain, R.N. Modeling T cell antigen discrimination based on feedback control of digital ERK responses. PLoS Biol. 3, e356 (2005).

    Article  PubMed  PubMed Central  Google Scholar 

  19. Li, Q.J. et al. miR-181a is an intrinsic modulator of T cell sensitivity and selection. Cell 129, 147–161 (2007).

    Article  CAS  PubMed  Google Scholar 

  20. Bettini, M.L. & Kersh, G.J. MAP kinase phosphatase activity sets the threshold for thymocyte positive selection. Proc. Natl. Acad. Sci. USA 104, 16257–16262 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Guan, K.L. & Butch, E. Isolation and characterization of a novel dual specific phosphatase, HVH2, which selectively dephosphorylates the mitogen-activated protein kinase. J. Biol. Chem. 270, 7197–7203 (1995).

    Article  CAS  PubMed  Google Scholar 

  22. Zhang, Y. et al. Regulation of innate and adaptive immune responses by MAP kinase phosphatase 5. Nature 430, 793–797 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. Miller, R.A., Garcia, G., Kirk, C.J. & Witkowski, J.M. Early activation defects in T lymphocytes from aged mice. Immunol. Rev. 160, 79–90 (1997).

    Article  CAS  PubMed  Google Scholar 

  24. Molina, G. et al. Zebrafish chemical screening reveals an inhibitor of Dusp6 that expands cardiac cell lineages. Nat. Chem. Biol. 5, 680–687 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Yager, E.J. et al. Age-associated decline in T cell repertoire diversity leads to holes in the repertoire and impaired immunity to influenza virus. J. Exp. Med. 205, 711–723 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Cicin-Sain, L. et al. Loss of naive T cells and repertoire constriction predict poor response to vaccination in old primates. J. Immunol. 184, 6739–6745 (2010).

    Article  CAS  PubMed  Google Scholar 

  27. Clambey, E.T., van Dyk, L.F., Kappler, J.W. & Marrack, P. Non-malignant clonal expansions of CD8+ memory T cells in aged individuals. Immunol. Rev. 205, 170–189 (2005).

    Article  CAS  PubMed  Google Scholar 

  28. Messaoudi, I., Lemaoult, J., Guevara-Patino, J.A., Metzner, B.M. & Nikolich-Zugich, J. 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 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Saurwein-Teissl, M. et al. Lack of antibody production following immunization in old age: association with CD8+CD28− T cell clonal expansions and an imbalance in the production of TH1 and TH2 cytokines. J. Immunol. 168, 5893–5899 (2002).

    Article  CAS  PubMed  Google Scholar 

  30. Goronzy, J.J. et al. Value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals. J. Virol. 75, 12182–12187 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Goronzy, J.J., Lee, W.W. & Weyand, C.M. Aging and T-cell diversity. Exp. Gerontol. 42, 400–406 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sadighi Akha, A.A. & Miller, R.A. Signal transduction in the aging immune system. Curr. Opin. Immunol. 17, 486–491 (2005).

    Article  CAS  PubMed  Google Scholar 

  33. Gorgas, G., Butch, E.R., Guan, K.L. & Miller, R.A. Diminished activation of the MAP kinase pathway in CD3-stimulated T lymphocytes from old mice. Mech. Ageing Dev. 94, 71–83 (1997).

    Article  CAS  PubMed  Google Scholar 

  34. Ledbetter, J.A. et al. Signal transduction through CD4 receptors: stimulatory vs. inhibitory activity is regulated by CD4 proximity to the CD3/T cell receptor. Eur. J. Immunol. 18, 525–532 (1988).

    Article  CAS  PubMed  Google Scholar 

  35. Grossmann, A., Ledbetter, J.A. & Rabinovitch, P.S. Reduced proliferation in T lymphocytes in aged humans is predominantly in the CD8+ subset, and is unrelated to defects in transmembrane signaling which are predominantly in the CD4+ subset. Exp. Cell Res. 180, 367–382 (1989).

    Article  CAS  PubMed  Google Scholar 

  36. Lee, W.W. et al. Age-dependent signature of metallothionein expression in primary CD4 T cell responses is due to sustained zinc signaling. Rejuvenation Res. 11, 1001–1011 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Boyman, O., Letourneau, S., Krieg, C. & Sprent, J. Homeostatic proliferation and survival of naive and memory T cells. Eur. J. Immunol. 39, 2088–2094 (2009).

    Article  CAS  PubMed  Google Scholar 

  38. Aspinall, R., Del Giudice, G., Effros, R.B., Grubeck-Loebenstein, B. & Sambhara, S. Challenges for vaccination in the elderly. Immun. Ageing 4, 9 (2007).

    Article  PubMed  PubMed Central  Google Scholar 

  39. Khurana, S. et al. Vaccines with MF59 adjuvant expand the antibody repertoire to target protective sites of pandemic avian H5N1 influenza virus. Sci. Transl. Med. 2, 15ra15 (2010).

    Article  Google Scholar 

  40. Del Giudice, G. et al. An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine. Vaccine 24, 3063–3065 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Galli, G. et al. Adjuvanted H5N1 vaccine induces early CD4+ T cell response that predicts long-term persistence of protective antibody levels. Proc. Natl. Acad. Sci. USA 106, 3877–3882 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Couch, R.B. et al. Safety and immunogenicity of a high dosage trivalent influenza vaccine among elderly subjects. Vaccine 25, 7656–7663 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Oxman, M.N. et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N. Engl. J. Med. 352, 2271–2284 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

J.J.G. was supported by US National Institutes of Health grants U19 AI090019, R01 AG015043 and U19 AI057266, and C.M.W. was supported by US National Institutes of Health grants R01 AR042527, R01 EY011916, R01 AI044142 and PO1 HL058000. Antibody to PTPN22 was a gift from A.C. Chan (Genentech).

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Authors and Affiliations

  1. Department of Medicine, Stanford University School of Medicine, Stanford, California, USA

    Guangjin Li, Mingcan Yu, Eswar Krishnan, Cornelia M Weyand & Jörg J Goronzy

  2. Palo Alto Department of Veterans Affairs Health Care System, Palo Alto, California, USA

    Guangjin Li, Mingcan Yu, Eswar Krishnan, Cornelia M Weyand & Jörg J Goronzy

  3. Department of Microbiology and Immunology, Seoul National University College of Medicine, Seoul, South Korea

    Won-Woo Lee

  4. Department of Developmental Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, USA

    Michael Tsang

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Contributions

G.L., M.Y., W.-W.L., C.M.W. and J.J.G. designed experiments and analyzed data. G.L., M.Y. and W.-W.L. generated data. M.T. provided BCI and advice in the design of the DUSP6 inhibition experiments. E.K. recruited and clinically phenotyped healthy elderly individuals. G.L. and J.J.G. wrote the manuscript.

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Correspondence to Jörg J Goronzy.

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Li, G., Yu, M., Lee, WW. et al. Decline in miR-181a expression with age impairs T cell receptor sensitivity by increasing DUSP6 activity. Nat Med 18, 1518–1524 (2012). https://doi.org/10.1038/nm.2963

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