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:

Immune Recovery

Reconstitution of γδ T cell repertoire diversity after human allogeneic hematopoietic cell transplantation and the role of peripheral expansion of mature T cell population in the graft

Bone Marrow Transplantation volume 26, pages 177–185 (2000)Cite this article

Abstract

We have examined the reconstitution of γδ T cell repertoire diversity after human allogeneic hematopoietic cell transplantation using a polymerase chain reaction (PCR)-based complementarity-determining region (CDR) 3 size spectratyping and DNA sequencing. The CDR3 complexity in the variable region of the T cell receptor (TCR)-δ chain was different amongst the individuals studied. Furthermore, CDR3 size distribution patterns of allogeneic hematopoietic cell transplant recipients were almost completely recovered by a few months after transplantation. In some patients, clonal predominance of the TCRDV1+ T cells became evident during the period after transplantation. In one particular donor/recipient pair, clonal predominance of TCRDV1+ T cells was already present in blood lymphocytes of the donor, and was also observed in the recipient after transplantation. Using this donor/recipient pair, we have questioned whether γδ T cell regeneration occurs via the peripheral expansion of mature T cells in the graft. In the donor lymphocytes, two expanding γδ T cell clones, which were demonstrated by CDR3 sequences of the TCR-δ chain, were recognized. These two clones were identified in the T cells from the recipient post transplant, but not before transplantation. One of the two clones was still detectable 1½ years after the transplant procedure. These results strongly suggest that peripheral expansion of mature T cells in the graft is the principal pathway of γδ T cell regeneration after allogeneic hematopoietic cell transplantation in adults. Bone Marrow Transplantation (2000) 26, 177–185.

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
Figure 6

Similar content being viewed by others

References

  1. McVay LD, Carding SR . Extrathymic origin of human γδ T cells during fetal development J Immunol 1996 157: 2873–2882

    CAS  PubMed  Google Scholar 

  2. McVay LD, Jaswal SS, Kennedy C et al. The generation of human γδ T cell repertoires during fetal development J Immunol 1998 160: 5851–5860

    CAS  PubMed  Google Scholar 

  3. Wells FB, Tatsumi Y, Bluestone JA et al. Phenotypic and functional analysis of positive selection in the γδ T cell lineage J Exp Med 1993 177: 1061–1070

    Article  CAS  PubMed  Google Scholar 

  4. Dent AL, Matis LA, Hooshmand F et al. Self-reactive γδ T cells are eliminated in the thymus Nature 1990 343: 714–719

    Article  CAS  PubMed  Google Scholar 

  5. Mackall CL, Hakim FT, Gress RE . T-cell regeneration: all repertoires are not created equal Immunol Today 1997 18: 245–251

    Article  CAS  PubMed  Google Scholar 

  6. Mackall CL, Granger L, Sheard MA et al. T-cell regeneration after bone marrow transplantation: differential CD45 isoform expression on thymic-derived versus thymic-independent progeny Blood 1993 82: 2585–2594

    CAS  PubMed  Google Scholar 

  7. Bomberger C, Singh-Jairam M, Rodey G et al. Lymphoid reconstitution after autologous PBSC transplantation with FACS-sorted CD34+ hematopoietic progenitors Blood 1998 91: 2588–2600

    CAS  PubMed  Google Scholar 

  8. Gorski J, Yassai M, Zhu X et al. Circulating T cell repertoire complexity in normal individuals and bone marrow recipients analyzed by CDR3 size spectratyping J Immunol 1994 152: 5109–5119

    CAS  PubMed  Google Scholar 

  9. Hirokawa M, Horiuchi T, Kitabayashi A, et al. Delayed recovery of CDR3 complexity of the T cell receptor-β chain in recipients of allogeneic bone marrow transplants who had virus-associated interstitial pneumonia: monitor of T cell function by CDR3 spectratyping J Allergy Clin Immunol (in press)

  10. Davis MM, Bjorkman PJ . T-cell antigen receptor genes and T-cell recognition Nature 1988 334: 395–402

    Article  CAS  PubMed  Google Scholar 

  11. Storb R, Deeg HJ, Whitehead J et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft-versus-host disease after marrow transplantation for leukemia New Engl J Med 1986 314: 729–735

    Article  CAS  PubMed  Google Scholar 

  12. Glucksberg H, Storb R, Fefer A et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors Transplantation 1974 18: 295–304

    Article  CAS  PubMed  Google Scholar 

  13. Boeckh M, Bowden RA, Goodrich JM et al. Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation Blood 1992 80: 1358–1364

    CAS  PubMed  Google Scholar 

  14. Yau JC, Dimopoulos MA, Huan SD et al. Prophylaxis of cytomegalovirus infection with ganciclovir in allogeneic marrow transplantation Eur J Haematol 1991 47: 371–376

    Article  CAS  PubMed  Google Scholar 

  15. Horiuchi T, Hirokawa M, Satoh K et al. Clonal expansion of γδ-T lymphocytes in an HTLV-I carrier, associated with chronic neutropenia and rheumatoid arthritis Ann Hematol 1999 78: 101–104

    Article  CAS  PubMed  Google Scholar 

  16. Tsuruta Y, Iwagami S, Furue S et al. Detection of human T cell receptor cDNAs (α, β, γ and δ) by ligation of a universal adaptor to variable region J Immunol Meth 1993 161: 7–21

    Article  CAS  Google Scholar 

  17. Lum LG . The kinetics of immune reconstitution after human marrow transplantation Blood 1987 69: 369–380

    CAS  PubMed  Google Scholar 

  18. Parkman R, Weinberg K . Immunological reconstitution following hematopoietic stem cell transplantation. In: Thomas ED, Blume KG, Forman SJ (eds) Hematopoietic Cell Transplantation Blackwell Science: Malden 1999 pp704–711

    Google Scholar 

  19. Viale M, Ferrini S, Bacigalupo A . TCR γδ positive lymphocytes after allogeneic bone marrow transplantation Bone Marrow Transplant 1992 10: 249–250

    CAS  PubMed  Google Scholar 

  20. Dechanet J, Merville P, Lim A et al. Implication of γδ T cells in the human immune response to cytomegalovirus J Clin Invest 1999 103: 1437–1449

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Dechanet J, Merville P, Berge F et al. Major expansion of γδ T lymphocytes following cytomegalovirus infection in kidney allograft recipients J Infect Dis 1999 179: 1–8

    Article  CAS  PubMed  Google Scholar 

  22. Mombaerts P, Arnoldi J, Russ F et al. Different roles of αβ and γδ T cells in immunity against an intracellular bacterial pathogen Nature 1993 365: 53–56

    Article  CAS  PubMed  Google Scholar 

  23. Ladel CH, Blum C, Dreher A et al. Protective role of γδ T cells and αβ T cells in tuberculosis Eur J Immunol 1995 25: 2877–2881

    Article  CAS  PubMed  Google Scholar 

  24. Hiromatsu K, Yoshikai Y, Matsuzaki G et al. A protective role of γδ T cells in primary infection with Listeria monocytogenes in mice J Exp Med 1992 175: 49–56

    Article  CAS  PubMed  Google Scholar 

  25. Lamb LS Jr, Henslee-Downey PJ, Parrish RS et al. Increased frequency of TCR γδ+ T cells in disease-free survivors following T cell-depleted, partially mismatched, related donor bone marrow transplantation for leukemia J Hematother 1996 5: 503–509

    Article  PubMed  Google Scholar 

  26. Pfeffer K, Schoel B, Gulle H et al. Primary responses of human T cells to mycobacteria: a frequent set of γδ+ T cells are stimulated by protease-resistant ligands Eur J Immunol 1990 20: 1175–1179

    Article  CAS  PubMed  Google Scholar 

  27. Tanaka Y, Sano S, Nieves E et al. Nonpeptide ligands for human γδ T cells Proc Natl Acad Sci USA 1994 91: 8175–8179

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Constant P, Davodeau F, Peyrat MA et al. Stimulation of human γδ T cells by nonpeptidic mycobacterial ligands Science 1994 264: 267–270

    Article  CAS  PubMed  Google Scholar 

  29. Schild H, Mavaddat N, Litzenberger C et al. The nature of major histocompatibility complex recognition by γδ T cells Cell 1994 76: 29–37

    Article  CAS  PubMed  Google Scholar 

  30. Weitraub BC, Jackson MR, Hedrick SM . γδ T cells can recognize nonclassical MHC in the absence of conventional antigenic peptides J Immunol 1994 153: 3051–3058

    Google Scholar 

  31. Zaia JA . Infections. In: Blume KG, Petz LD (eds) Clinical Bone Marrow Transplantation Churchill Livingstone: New York 1983 pp131–176

    Google Scholar 

  32. Navari RM, Sullivan KM, Springmeyer SC et al. Mycobacterial infections in marrow transplant patients Transplantation 1983 36: 509–513

    Article  CAS  PubMed  Google Scholar 

  33. Aljurf M, Gyger M, Alrajhi A et al. Mycobacterium tuberculosis infection in allogeneic bone marrow transplantation patients Bone Marrow Transplant 1999 24: 551–554

    Article  CAS  PubMed  Google Scholar 

  34. Chang J, Powles R, Mehta J et al. Listeriosis in bone marrow transplant recipients: incidence, clinical features, and treatment Clin Infect Dis 1995 21: 1289–1290

    Article  CAS  PubMed  Google Scholar 

  35. Rocha B, Vassalli P, Guy-Grand D . The extrathymic T-cell development pathway Immunol Today 1992 13: 449–454

    Article  CAS  PubMed  Google Scholar 

  36. Sato K, Ohtsuka K, Hasegawa K et al. Evidence for extrathymic generation of intermediate T cell receptor cells in the liver revealed in thymectomized, irradiated mice subjected to bone marrow transplantation J Exp Med 1995 182: 759–767

    Article  CAS  PubMed  Google Scholar 

  37. Dejbakhsh-Jones S, Jerabek L, Weissman IL, Strober S . Extrathymic maturation of αβ T cells from hemopoietic stem cells J Immunol 1995 155: 3338–3344

    CAS  PubMed  Google Scholar 

  38. Bell EB, Sparhott SM, Drayson MT, Ford WL . The stable and permanent expansion of functional T lymphocytes in athymic nude rats after a single injection of mature T cells J Immunol 1987 139: 1379–1384

    CAS  PubMed  Google Scholar 

  39. Rocha BB . Population kinetics of precursors of IL-2-producing peripheral T lymphocytes: evidence for short life expectancy, continuous renewal, and post-thymic expansion J Immunol 1987 139: 365–372

    CAS  PubMed  Google Scholar 

  40. Rocha B, Dautigny N, Pereira P . Peripheral T lymphocytes: expansion potential and homeostatic regulation of pool sizes and CD4/CD8 ratios in vivo Eur J Immunol 1989 19: 905–911

    Article  CAS  PubMed  Google Scholar 

  41. Tanchot C, Rocha B . The organization of mature T-cell pools Immunol Today 1998 19: 575–579

    Article  CAS  PubMed  Google Scholar 

  42. Kisielow P, Miazek A . Positive selection of T cells: rescue from programmed cell death and differentiation require continual engagement of the T cell receptor J Exp Med 1995 181: 1975–1984

    Article  CAS  PubMed  Google Scholar 

  43. Kirberg J, Berns A, von Boehmer H . Peripheral T cell survival requires continual ligation of the T cell receptor to major histocompatibility complex-encoded molecules J Exp Med 1997 186: 1269–1275

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Hou S, Hyland L, Ryan KW et al. Virus-specific CD8+ T-cell memory determined by clonal burst size Nature 1994 369: 652–654

    Article  CAS  PubMed  Google Scholar 

  45. Lau LL, Jamieson BD, Somasundaram T, Ahmed R . Cytotoxic T-cell memory without antigen Nature 1994 369: 648–652

    Article  CAS  PubMed  Google Scholar 

  46. Kitabayashi A, Hirokawa M, Horiuchi T et al. Late-onset herpes simplex virus-associated interstitial pneumonia after allogeneic bone marrow transplantation Bone Marrow Transplant 2000 25: 225–226

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We are grateful to the hematology staff at Akita University Medical Center for their treatment of the patients included in this study. This work was supported by grants from the Ministry of Education, Science, Sports and Culture of Japan (Grant No. 08670508, 10670932), the Yamashita Taro-Kensho Memorial Foundation and the Uehara Memorial Foundation.

Author information

Authors and Affiliations

  1. Department of Internal Medicine III, Akita University School of Medicine, Japan

    M Hirokawa, T Horiuchi, Y Kawabata, A Kitabayashi & AB Miura

Authors
  1. M Hirokawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. T Horiuchi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Y Kawabata
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Kitabayashi
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. AB Miura
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hirokawa, M., Horiuchi, T., Kawabata, Y. et al. Reconstitution of γδ T cell repertoire diversity after human allogeneic hematopoietic cell transplantation and the role of peripheral expansion of mature T cell population in the graft. Bone Marrow Transplant 26, 177–185 (2000). https://doi.org/10.1038/sj.bmt.1702478

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1702478

Keywords

This article is cited by

Search

Advanced search

Quick links