Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Article
  • Published:

Myelodysplasias

Altered naive and memory CD4+ T-cell homeostasis and immunosenescence characterize younger patients with myelodysplastic syndrome

Leukemia volume 23, pages 1288–1296 (2009)Cite this article

Abstract

Response to immunosuppressive therapy (IST) in younger patients with myelodysplastic syndrome (MDS) has been linked to a T-cell-dominant autoimmune process that impairs hematopoiesis. Analysis of the age-adjusted CD4:CD8 ratio in 76 MDS patients compared with 54 healthy controls showed that inadequate CD4+, rather than expansion of CD8+ T cells, was associated with a lower ratio in a group that included both lower and higher risk MDS patients defined by the International Prognostic Scoring System. In younger MDS patients, naive and memory phenotypes defined by CD45RA and CD62L display showed depletion of naive CD4+ and CD8+ T cells, suggesting a possible relationship to IST responsiveness. To determine the correlation between T-cell subset distribution, T-cell turnover and autoimmunity, a cohort of 20 patients were studied before and after IST. The CD4:CD8 ratio correlated inversely with the proliferative T-cell index before treatment in IST-responsive patients, suggesting that proliferation may be linked to accelerated CD4+ T-cell turnover and hematopoietic failure. Our data show seminal findings that both CD4+ and CD8+ T-cell subsets are dysregulated in MDS. Association between these T-cell defects and response to IST suggests that aberrant T-cell homeostasis and chronic activation are critical determinants influencing autoimmune hematopoietic suppression in younger patients.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  1. Lim ZY, Cook G, Johnson PR, Zuckerman M, Marks D, Wiltshire H et al. Low IPSS score and bone marrow hypocellularity in MDS patients predict hematological responses to antithymocyte globulin. Leukemia 2007; 21: 1436–1441.

    Article  CAS  PubMed  Google Scholar 

  2. Sun M, Zhang J, Liu S, Liu Y, Zheng D . Sp1 is involved in 8-chloro-adenosine-upregulated death receptor 5 expression in human hepatoma cells. Oncol Rep 2008; 19: 177–185.

    CAS  PubMed  Google Scholar 

  3. Young NS . Immunosuppressive treatment of acquired aplastic anemia and immune-mediated bone marrow failure syndromes. Int J Hematol 2002; 75: 129–140.

    Article  CAS  PubMed  Google Scholar 

  4. Molldrem JJ, Jiang YZ, Stetler-Stevenson M, Mavroudis D, Hensel N, Barrett AJ . Haematological response of patients with myelodysplastic syndrome to antithymocyte globulin is associated with a loss of lymphocyte-mediated inhibition of CFU-GM and alterations in T-cell receptor Vbeta profiles. Br J Haematol 1998; 102: 1314–1322.

    Article  CAS  PubMed  Google Scholar 

  5. Kochenderfer JN, Kobayashi S, Wieder ED, Su C, Molldrem JJ . Loss of T-lymphocyte clonal dominance in patients with myelodysplastic syndrome responsive to immunosuppression. Blood 2002; 100: 3639–3645.

    Article  CAS  PubMed  Google Scholar 

  6. Epling-Burnette PK, Zhong B, Bai F, Jiang K, Bail RD, Garcia R et al. Inhibition of STAT3 signaling leads to apoptosis of leukemic large granular lymphocytes and decreased Mcl-1 expression. J Clin Invest 2001; 107: 351–362.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Maldonado A, Muller YM, Thomas P, Bojczuk P, O'Connors C, Katsikis PD . Decreased effector memory CD45RA+ CD62L– CD8+ T cells and increased central memory CD45RA– CD62L+ CD8+ T cells in peripheral blood of rheumatoid arthritis patients. Arthritis Res Ther 2003; 5: R91–R96.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Rabin RL, Roederer M, Maldonado Y, Petru A, Herzenberg LA, Herzenberg LA . Altered representation of naive and memory CD8T cell subsets in HIV-infected children. J Clin Invest 1995; 95: 2054–2060.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Hazenberg SA, Otto SA, Cohen Stuart JW, Verschuren MC, Borleffs JC, Boucher CA et al. T-cell division in human immunodeficiency virus (HIV)-1 infection is mainly due to immune activation: a longitudinal analysis in patients before and during highly active antiretroviral therapy (HAART). Blood 2000; 95: 249–255.

    CAS  PubMed  Google Scholar 

  10. Hellerstein M, Hanley MB, Cesar D, Siler S, Papageorgopoulos C, Wieder E et al. Directly measured kinetics of circulating T lymphocytes in normal and HIV-1-infected humans. Nat Med 1999; 5: 83–89.

    Article  CAS  PubMed  Google Scholar 

  11. Bennett JM, Komrokji RS . The myelodysplastic syndromes: diagnosis, molecular biology and risk assessment. Hematology 2005; 10 (Suppl 1): 258–269.

    Article  CAS  PubMed  Google Scholar 

  12. Sokol RJ, Hewitt S, Booker DJ . Erythrocyte autoantibodies autoimmune haemolysis, myelodysplastic syndromes. J Clin Pathol 1989; 42: 1088–1091.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Kook H, Zeng W, Guibin C, Kirby M, Young NS, Maciejewski JP . Increased cytotoxic T cells with effector phenotype in aplastic anemia and myelodysplasia. Exp Hematol 2001; 29: 1270–1277.

    Article  CAS  PubMed  Google Scholar 

  14. Saunthararajah Y, Molldrem JL, Rivera M, Williams A, Stetler-Stevenson M, Sorbara L et al. Coincident myelodysplastic syndrome and T-cell large granular lymphocytic disease: clinical and pathophysiological features. Br J Haematol 2001; 112: 195–200.

    Article  CAS  PubMed  Google Scholar 

  15. Wang HQ, Shao ZH, Shi J, Cao YR, Liu H, Bai J et al. Burden of abnormal hematopoietic clone in patients with myelodysplastic syndromes. Chin Med Sci J 2006; 21: 99–103.

    CAS  PubMed  Google Scholar 

  16. Okamoto T, Okada M, Mori A, Saheki K, Takatsuka H, Wada H et al. Correlation between immunological abnormalities and prognosis in myelodysplastic syndrome patients. Int J Hematol 1997; 66: 345–351.

    Article  CAS  PubMed  Google Scholar 

  17. Sallusto F, Lenig D, Forster R, Lipp M, Lanzavecchia A . Two subsets of memory T lymphocytes with distinct homing potentials and effector functions. Nature 1999; 401: 708–712.

    Article  CAS  PubMed  Google Scholar 

  18. De Rosa SC, Herzenberg LA, Herzenberg LA, Roederer M . 11-color, 13-parameter flow cytometry: identification of human naive T cells by phenotype, function, and T-cell receptor diversity. Nat Med 2001; 7: 245–248.

    Article  CAS  PubMed  Google Scholar 

  19. Champagne P, Ogg GS, King AS, Knabenhan C, Ellefsen K, Nobile M et al. Skewed maturation of memory HIV-specific CD8T lymphocytes. Nature 2001; 410: 106–111.

    Article  CAS  PubMed  Google Scholar 

  20. Naylor K, Li G, Vallejo AN, Lee WW, Koetz K, Bryl E et al. The influence of age on T cell generation and TCR diversity. J Immunol 2005; 174: 7446–7452.

    Article  CAS  PubMed  Google Scholar 

  21. Czesnikiewicz-Guzik M, Lee WW, Cui D, Hiruma Y, Lamar DL, Yang ZZ et al. T cell subset-specific susceptibility to aging. Clin Immunol 2008; 127: 107–118.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Goldrath AW, Bevan MJ . Selecting and maintaining a diverse T-cell repertoire. Nature 1999; 402: 255–262.

    Article  CAS  PubMed  Google Scholar 

  23. Schwab R, Szabo P, Manavalan JS, Weksler ME, Posnett DN, Pannetier C et al. Expanded CD4+ and CD8+ T cell clones in elderly humans. J Immunol 1997; 158: 4493–4499.

    CAS  PubMed  Google Scholar 

  24. Krupica Jr T, Fry TJ, Mackall CL . Autoimmunity during lymphopenia: a two-hit model. Clin Immunol 2006; 120: 121–128.

    Article  CAS  PubMed  Google Scholar 

  25. Marleau AM, Sarvetnick N . T cell homeostasis in tolerance and immunity. J Leukoc Biol 2005; 78: 575–584.

    Article  CAS  PubMed  Google Scholar 

  26. Goronzy JJ, Weyand CM . Rheumatoid arthritis. Immunol Rev 2005; 204: 55–73.

    Article  CAS  PubMed  Google Scholar 

  27. Fulop Jr T, Larbi A, Dupuis G, Pawelec G . Ageing, autoimmunity and arthritis: perturbations of TCR signal transduction pathways with ageing - a biochemical paradigm for the ageing immune system. Arthritis Res Ther 2003; 5: 290–302.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Cheson BD, Greenberg PL, Bennett JM, Lowenberg B, Wijermans PW, Nimer SD et al. Clinical application and proposal for modification of the International Working Group (IWG response criteria in myelodysplasia. Blood 2006; 108: 419–425.

    Article  CAS  PubMed  Google Scholar 

  29. Sloand EM, Wu CO, Greenberg P, Young N, Barrett J . Factors affecting response and survival in patients with myelodysplasia treated with immunosuppressive therapy. J Clin Oncol 2008; 26: 2505–2511.

    Article  PubMed  Google Scholar 

  30. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  31. Colmegna I, Diaz-Borjon A, Fujii H, Schaefer L, Goronzy JJ, Weyand CM . Defective proliferative capacity and accelerated telomeric loss of hematopoietic progenitor cells in rheumatoid arthritis. Arthritis Rheum 2008; 58: 990–1000.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Loughran Jr P . Anemia in lymphoproliferative disorders. Cancer Control 1998; 5: 51–53.

    Article  PubMed  Google Scholar 

  33. Starkebaum G, Loughran Jr TP, Gaur LK, Davis P, Nepom BS . Immunogenetic similarities between patients with Felty′s syndrome and those with clonal expansions of large granular lymphocytes in rheumatoid arthritis. Arthritis Rheum 1997; 40: 624–626.

    Article  CAS  PubMed  Google Scholar 

  34. Molldrem JJ, Caples M, Mavroudis D, Plante M, Young NS, Barrett AJ . Antithymocyte globulin for patients with myelodysplastic syndrome. Br J Haematol 1997; 99: 699–705.

    Article  CAS  PubMed  Google Scholar 

  35. Biesma DH, van den Tweel JG, Verdonck LF . Immunosuppressive therapy for hypoplastic myelodysplastic syndrome. Cancer 1997; 79: 1548–1551.

    Article  CAS  PubMed  Google Scholar 

  36. Steensma DP, Tefferi A . The myelodysplastic syndrome(s): a perspective and review highlighting current controversies. Leuk Res 2003; 27: 95–120.

    Article  PubMed  Google Scholar 

  37. List AF, Vardiman J, Issa JP, DeWitte TM . Myelodysplastic syndromes. Hematology (Am Soc Hematol Educ Program) 2004; 297–317.

    Article  Google Scholar 

  38. Molldrem JJ, Leifer E, Bahceci E, Saunthararajah Y, Rivera M, Dunbar C et al. Antithymocyte globulin for treatment of the bone marrow failure associated with myelodysplastic syndromes. Ann Intern Med 2002; 137: 156–163.

    Article  PubMed  Google Scholar 

  39. Sloand EM, Mainwaring L, Fuhrer M, Ramkissoon S, Risitano AM, Keyvanafar K et al. Preferential suppression of trisomy 8 compared with normal hematopoietic cell growth by autologous lymphocytes in patients with trisomy 8 myelodysplastic syndrome. Blood 2005; 106: 841–851.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Hazenberg MD, Otto SA, Cohen Stuart JW, Verschuren MC, Borleffs JC . Increased cell division but not thymic dysfunction rapidly affects the T-cell receptor excision circle content of the naive T cell population in HIV-1 infection. Nat Med 2000; 6: 1036–1042.

    Article  CAS  PubMed  Google Scholar 

  41. Goronzy JJ, Weyand CM . Thymic function and peripheral T-cell homeostasis in rheumatoid arthritis. Trends Immunol 2001; 22: 251–255.

    Article  CAS  PubMed  Google Scholar 

  42. Weyand CM, Goronzy JJ . T-cell responses in rheumatoid arthritis: systemic abnormalities-local disease. Curr Opin Rheumatol 1999; 11: 210–217.

    Article  CAS  PubMed  Google Scholar 

  43. Sloand EM, Kim S, Fuhrer M, Risitano AM, Nakamura R, Maciejewski JP et al. Fas-mediated apoptosis is important in regulating cell replication and death in trisomy 8 hematopoietic cells but not in cells with other cytogenetic abnormalities. Blood 2002; 100: 4427–4432.

    Article  CAS  PubMed  Google Scholar 

  44. Gersuk GM, Beckham C, Loken MR, Kiener P, Anderson JE, Farrand A et al. A role for tumour necrosis factor-alpha, Fas and Fas-Ligand in marrow failure associated with myelodysplastic syndrome. Br J Haematol 1998; 103: 176–188.

    Article  CAS  PubMed  Google Scholar 

  45. Powers MP, Nishino H, Luo Y, Raza A, Vanguri A, Rice L et al. Polymorphisms in TGFbeta and TNFalpha are associated with the myelodysplastic syndrome phenotype. Arch Pathol Lab Med 2007; 131: 1789–1793.

    CAS  PubMed  Google Scholar 

  46. Galili N, Cerny J, Raza A . Current treatment options: impact of cytogenetics on the course of myelodysplasia. Curr Treat Options Oncol 2007; 8: 117–128.

    Article  PubMed  Google Scholar 

  47. Reza S, Dar S, Andric T, Qawi H, Mundle S, Shetty V et al. Biologic characteristics of 164 patients with myelodysplastic syndromes. Leuk Lymphoma 1999; 33: 281–287.

    Article  CAS  PubMed  Google Scholar 

  48. Reza S, Shetty V, Dar S, Qawi H, Raza A . Tumor necrosis factor-alpha levels decrease with anticytokine therapy in patients with myelodysplastic syndromes. J Interferon Cytokine Res 1998; 18: 871–877.

    Article  CAS  PubMed  Google Scholar 

  49. Clarke SR, Rudensky AY . Survival and homeostatic proliferation of naive peripheral CD4+ T cells in the absence of self peptide: MHC complexes. J Immunol 2000; 165: 2458–2464.

    Article  CAS  PubMed  Google Scholar 

  50. Lim HW, Kim CH . Loss of IL-7 receptor alpha on CD4+ T cells defines terminally differentiated B cell-helping effector T cells in a B cell-rich lymphoid tissue. J Immunol 2007; 179: 7448–7456.

    Article  CAS  PubMed  Google Scholar 

  51. Chiu WK, Fann M, Weng NP . Generation and growth of CD28nullCD8+ memory T cells mediated by IL-15 and its induced cytokines. J Immunol 2006; 177: 7802–7810.

    Article  CAS  PubMed  Google Scholar 

  52. Stockinger B, Kassiotis G, Bourgeois C . Homeostasis and T cell regulation. Curr Opin Immunol 2004; 16: 775–779.

    Article  CAS  PubMed  Google Scholar 

  53. Setoguchi R, Hori S, Takahashi T, Sakaguchi S . Homeostatic maintenance of natural Foxp3(+) CD25(+) CD4(+) regulatory T cells by interleukin (IL)-2 and induction of autoimmune disease by IL-2 neutralization. J Exp Med 2005; 201: 723–735.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Neujahr DC, Chen C, Huang X, Markmann JF, Cobbold S, Waldman H et al. Accelerated memory cell homeostasis during T cell depletion and approaches to overcome it. J Immunol 2006; 176: 4632–4639.

    Article  CAS  PubMed  Google Scholar 

  55. Calzascia T, Pellegrini M, Lin A, Garza KM, Elford AR, Shahinian A et al. CD4T cells, lymphopenia, and IL-7 in a multistep pathway to autoimmunity. Proc Natl Acad Sci USA 2008; 105: 2999–3004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Dunham RM, Cervasi B, Brenchley JM, Albrecht H, Weintrob A, Sumpter B et al. CD127 and CD25 expression defines CD4+ T cell subsets that are differentially depleted during HIV infection. J Immunol 2008; 180: 5582–5592.

    Article  CAS  PubMed  Google Scholar 

  57. Vrabelova Z, Hrotekova Z, Hladikova Z, Bohmova K, Stechova K, Michalek J . CD 127- and FoxP3+ expression on CD25+CD4+ T regulatory cells upon specific diabetogeneic stimulation in high-risk relatives of type 1 diabetes mellitus patients. Scand J Immunol 2008; 67: 404–410.

    Article  CAS  PubMed  Google Scholar 

  58. Alves NL, van Leeuwen EM, Remmerswaal EB, Vrisekoop N, Tesselaar K, Roosnek E et al. A new subset of human naive CD8+ T cells defined by low expression of IL-7R alpha. J Immunol 2007; 179: 221–228.

    Article  CAS  PubMed  Google Scholar 

  59. Valencic E, Piscianz E, Tommasini A, Granzotto M . T cells stimulated in vitro have a suppressive function but do not contain only regulatory T cells. Clin Exp Immunol 2007; 150: 561–566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Catalfamo M, Tai X, Karpova T, McNally J, Henkart PA . TcR-induced regulated secretion leads to surface expression of CTLA-4 in CD4(+)CD25(+) T cells. Immunology 2008; 125: 70–79.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Kordasti SY, Ingram W, Hayden J, Darling D, Barber L, Afzal B et al. CD4+CD25high Foxp3+ regulatory T cells in myelodysplastic syndrome (MDS). Blood 2007; 110: 847–850.

    Article  CAS  PubMed  Google Scholar 

  62. King C, Ilic A, Koelsch K, Sarvetnick N . Homeostatic expansion of T cells during immune insufficiency generates autoimmunity. Cell 2004; 117: 265–277.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was conducted by Moffitt Cancer Center Malignant Hematology Program and partially supported by grants from the Veterans' Administration Hospital and NCI (CA112112-01). The project described was supported by U54RR019397-05 from the NIH. Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the NIH. We would like to thank the Flow Cytometry Core Facility for assistance with this project.

Author information

Authors and Affiliations

  1. Immunology Program at the H. Lee Moffitt Cancer Center, Tampa, FL, USA

    J X Zou, F Bai, J S Painter, S Wei & P K Epling-Burnette

  2. Division of Cancer Prevention and Control at the H. Lee Moffitt Cancer Center, Tampa, FL, USA

    D E Rollison

  3. Biostatistics Program at the H. Lee Moffitt Cancer Center, Tampa, FL, USA

    D Boulware & D-T Chen

  4. NIH, NHLBI, Hematology Branch, Bethesda, MD, USA

    E M Sloand & L V Pfannes

  5. Lowance Center for Human Immunology, Emory University School of Medicine, Atlanta, GA, USA

    J J Goronzy & P K Epling-Burnette

  6. Division of Hematologic Malignancies, H. Lee Moffitt Cancer Center, Tampa, FL, USA

    D Cosgrove & A F List

  7. James A. Haley VA Hospital, Tampa, FL, USA

    P K Epling-Burnette

Authors
  1. J X Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. D E Rollison
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. D Boulware
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. D-T Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. E M Sloand
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L V Pfannes
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J J Goronzy
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. F Bai
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. J S Painter
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. S Wei
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. D Cosgrove
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. A F List
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. P K Epling-Burnette
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to P K Epling-Burnette.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Zou, J., Rollison, D., Boulware, D. et al. Altered naive and memory CD4+ T-cell homeostasis and immunosenescence characterize younger patients with myelodysplastic syndrome. Leukemia 23, 1288–1296 (2009). https://doi.org/10.1038/leu.2009.14

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2009.14

Keywords

This article is cited by

Search

Advanced search

Quick links