Abstract
There are two major pathways for T-cell regeneration after allogeneic bone marrow transplantation; thymus-dependent T-cell differentiation of T-cell progenitors, and peripheral expansion of mature T cells in the graft. In order to learn to what extent the peripheral expansion of donor-derived mature T lymphocytes contributes to reconstitution of the TCRαβ+ T-cell repertoire after allogeneic bone marrow transplantation for adult myeloid leukemias, we pursued the fate of donor-derived T-cell clones using the amino-acid sequences of the complementarity-determining region 3 (CDR3) of the TCR-β chain as a clonal marker. Clonal expansion of TCRαβ+ T lymphocytes with specific TCRBV subfamilies was identified in donor blood. Identical T-cell clones were not found in blood from recipients before transplantation. The donor-derived T-cell clones were identified in the circulating blood from recipients a few months after allogeneic bone marrow transplantation, and they remained in the blood for 18 months after transplant in two recipients, and for 56 months in one. These results suggest that the peripheral expansion of mature T lymphocytes in the graft makes a significant contribution to post-transplant T-cell regeneration during the early period of transplantation in humans, and that mature T cells can survive in recipients for several years. Further investigation will be required to explore which antigens drive the expansion of T-cell clones in donors and recipients, and the mechanisms of maintaining homeostatic balance between the thymus-dependent pathway and the peripheral expansion of mature T cells in post-transplant T-cell regeneration.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Mackall CL, Hakim FT, Gress RE . T-cell regeneration: all repertoires are not created equal. Immunol Today 1997; 18: 245–251.
Mackall CL, Gress RE . Thymic aging and T-cell regeneration. Immunol Rev 1997; 160: 91–102.
Matsutani T, Yoshioka T, Tsuruta Y, Iwagami S, Toyosaki-Maeda T, Horiuchi T et al. Restricted usage of T-cell receptor α-chain variable region (TCRAV) and T-cell receptor β-chain variable region (TCRBV) repertoires after human allogeneic haematopoietic transplantation. Br J Haematol 2000; 109: 759–769.
Hirokawa M, Horiuchi T, Kitabayashi A, Kawabata Y, Matsutani T, Suzuki R 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 2000; 106: 32–39.
Horiuchi T, Hirokawa M, Kawabata Y, Kitabayashi A, Matsutani T, Yoshioka T et al. Identification of the T-cell clones expanding within both CD8+CD28+ and CD8+CD28− T-cell subsets in recipients of allogeneic hematopoietic cell grafts and its implication in post-transplant skewing of T-cell receptor repertoire. Bone Marrow Transplant 2001; 27: 731–739.
Hirokawa M, Matsutani T, Horiuchi T, Kawabata Y, Kitabayashi A, Yoshioka T et al. Extensive clonal expansion of T lymphocytes causes contracted diversity of the complementarity-determining region 3 and a skewing of T-cell receptor repertoires after allogeneic hematopoietic cell transplantation. Bone Marrow Transplant 2001; 27: 607–614.
Mackall CL, Bare CV, Granger LA, Sharrow SO, Titus JA, Gress RE . Thymic-independent T cell regeneration occurs via antigen-driven expansion of peripheral T cells resulting in a repertoire that is limited in diversity and prone to skewing. J Immunol 1996; 156: 4609–4616.
Hirokawa M, Horiuchi T, Kawabata Y, Kitabayashi A, Miura AB . Reconstitution of γδ T-cell repertoire diversity after human allogeneic hematopoietic cell transplantation and the role for peripheral expansion of mature T-cell population in the graft. Bone Marrow Transplant 2000; 26: 177–185.
Storb R, Deeg HJ, Whitehead J, Appelbaum F, Beatty P, Bensinger W et al. Methotrexate and cyclosporine compared with cyclosporine alone for prophylaxis of acute graft-versus-host disease after marrow transplantation for leukemias. N Engl J Med 1986; 314: 729–735.
Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HLA-matched sibling donors. Transplantation 1974; 18: 295–304.
Boeckh M, Bowden RA, Goodrich JM, Pettinger M, Meyers JD . Cytomegalovirus antigen detection in peripheral blood leukocytes after allogeneic marrow transplantation. Blood 1992; 80: 1358–1364.
Yau JC, Dimopoulos MA, Huan SD, Tarrand JJ, Spencer V, Spitzer G et al. Prophylaxis of cytomegalovirus infection with ganciclovir in allogeneic marrow transplantation. Eur J Haematol 1991; 47: 371–376.
Pannetier C, Cochet M, Darche S, Casrouge A, Zoller M, Kourilsky P . The sizes of the CDR3 hypervariable regions of the murine T-cell receptor beta chains vary as a function of the recombined germ-line segments. Proc Natl Acad Sci USA 1993; 90: 4319–4323.
Kitabayashi A, Hirokawa M, Hatano Y, Lee M, Kuroki J, Niitsu H et al. Granulocyte colony-stimulating factor down-regulates allogeneic immune responses by post-transcriptional inhibition of tumor necrosis factor-α production. Blood 1995; 86: 2220–2227.
Kawabata Y, Hirokawa M, Kitabayashi A, Horiuchi T, Kuroki J, Miura AB . Defective apoptotic signal transduction pathway downstream of caspase-3 in human B-lymphoma cells: a novel mechanism of nuclear apoptosis resistance. Blood 1999; 94: 3523–3530.
Yoshioka T, Matsutani T, Iwagami S, Tsuruta Y, Kaneshige T, Toyosaki T et al. Quantitative analysis of the usage of human T cell receptor alpha and beta chain variable regions by reverse dot blot hybridization. J Immunol Methods 1997; 201: 145–155.
Matsutani T, Yoshioka T, Tsuruta Y, Iwagami S, Suzuki R . Analysis of TVRAV and TCRBV repertoires in healthy individuals by microplate hybridization assay. Hum Immunol 1997; 56: 57–69.
Yoshioka T, Matsutani T, Iwagami S, Toyosaki-Maeda T, Yutsudo T, Tsuruta Y et al. Polyclonal expansion of TCRBV2 and TCRBV6-bearing T cells in patients with Kawasaki disease. Immunology 1999; 96: 465–472.
Tsuruta Y, Iwagami S, Furue S, Teraoka H, Yoshida T, Sakata T 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 Methods 1993; 161: 7–12.
Posnett DN, Sinha R, Kabak S, Russo C . Clonal populations of T cells in normal elderly humans: the T cell equivalent to ‘benign monoclonal gammapathy’. J Exp Med 1994; 179: 609–618.
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.
Khan N, Shariff N, Cobbold M, Bruton R, Ainsworth JA, Sinclair AJ et al. Cytomegalovirus seropositivity drives the CD8 T cell repertoire toward greater clonality in healthy elderly individuals. J Immunol 2002; 169: 1984–1992.
Kronenberg M, Siu G, Hood LE, Shastri N . The molecular genetics of the T-cell antigen receptor and T-cell antigen recognition. Annu Rev Immunol 1986; 4: 529–591.
MacDonald HR, Schneider R, Lees RK, Howe RC, Acha-Orbea H, Festenstein H et al. T-cell receptor Vβ use predicts reactivity and tolerance to Mlsa-encoded antigens. Nature 1988; 332: 40–45.
Kappler JW, Roehm N, Marrack P . T cell tolerance by clonal elimination in the thymus. Cell 1987; 49: 273–280.
Teh HS, Kisielow P, Scott B, Kishi H, Uematsu Y, Bluthmann H et al. Thymic major histocompatibility antigens and the α–β T cell receptor determine the CD4/CD8 phenotype of T cells. Nature 1988; 335: 229–233.
Sha WC, Nelson CA, Newberry RD, Kranz DM, Russell JH, Loh DY . Positive and negative selection of an antigen receptor on T cells in transgenic mice. Nature 1988; 336: 73–76.
Tayebi H, Tiberghien P, Ferrand C, Lienard A, Duperrier A, Cahn JY et al. Allogeneic peripheral blood stem cell transplantation results in less alteration of early T cell compartment homeostasis than bone marrow transplantation. Bone Marrow Transplant 2001; 27: 167–175.
Patel DD, Gooding ME, Parrott RE, Curtis KM, Haynes BF, Buckley RH . Thymic function after hematopoietic stem-cell transplantation for the treatment of severe combined immunodeficiency. N Engl J Med 2000; 342: 1325–1332.
Hazenberg MD, Otto SA, de Pauw ES, Roelofs H, Fibbe WE, Hamann D et al. T-cell receptor excision circle and T-cell dynamics after allogeneic stem cell transplantation are related to clinical events. Blood 2002; 99: 3449–3353.
Marmont AM, Horowitz MM, Gale RP, Sobocinski K, Ash RC, van Bekkum DW et al. T-cell depletion of HLA-identical transplants in leukemia. Blood 1991; 78: 2120–2130.
Horowitz MM, Gale RP, Sondel PM, Goldman JM, Kersey J, Kolb HJ et al. Graft-versus-leukemia reactions after bone marrow transplantation. Blood 1990; 75: 555–562.
Bacigalupo A, Soracco M, Vassallo F, Abate M, Van Lint MT, Gualandi F et al. Donor lymphocyte infusions (DLI) in patients with chronic myeloid leukemia following allogeneic bone marrow transplantation. Bone Marrow Transplant 1997; 19: 927–932.
Collins Jr RH, Shpilberg O, Drobyski WR, Porter DL, Giralt S, Champlin R et al. Donor leukocyte infusions in 140 patients with relapsed malignancy after allogeneic bone marrow transplantation. J Clin Oncol 1997; 15: 433–444.
Eder M, Battmer K, Kafert S, Stucki A, Ganser A, Hertenstein B . Monitoring of BCR-ABL expression using real-time RT-PCR in CML after bone marrow or peripheral blood stem cell transplantation. Leukemia 1999; 13: 1383–1389.
Khouri IF, Keating M, Korbling M, Przepiorka D, Anderlini P, O'Brien S et al. Transplant-lite: induction of graft-versus-malignancy using fludarabine-based nonablative chemotherapy and allogeneic blood progenitor-cell transplantation as treatment for lymphoid malignancies. J Clin Oncol 1998; 16: 2817–2824.
Badros A, Barlogie B, Siegel E, Cottler-Fox M, Zangari M, Fassas A et al. Improved outcome of allogeneic transplantation in high-risk multiple myeloma patients after nonmyeloablative conditioning. J Clin Oncol 2002; 20: 1295–1303.
Miyamura K, Barrett AJ, Kodera Y, Saito H . Minimal residual disease after bone marrow transplantation for chronic myelogenous leukemia and implications for graft-versus-leukemia effect: a review of recent results. Bone Marrow Transplant 1994; 14: 201–209.
Claret EJ, Alyea EP, Orsini E, Pickett CC, Collins H, Wang Y et al. Characterization of T cell repertoire in patients with graft-versus-leukemia after donor lymphocyte infusion. J Clin Invest 1997; 15: 100: 855–866.
Hirokawa M, Matsutani T, Saitoh H, Ichikawa Y, Kawabata Y, Horiuchi T et al. Distinct TCRAV and TCRBV repertoire and CDR3 sequence of T lymphocytes clonally expanded in blood and GVHD lesions after human allogeneic bone marrow transplantation. Bone Marrow Transplant 2002; 30: 915–923.
Kern F, Bunde T, Faulhaber N, Kiecker F, Khatamzas E, Rudawski IM et al. Cytomegalovirus (CMV) phosphoprotein 65 makes a large contribution to shaping the T cell repertoire in CMV-exposed individuals. J Infect Dis 2002; 185: 1709–1716.
Aubert G, Hassan-Walker AF, Madrigal JA, Emery VC, Morte C, Grace S et al. Cytomegalovirus-specific cellular immune responses and viremia in recipients of allogeneic stem cell transplants. J Infect Dis 200; 184: 955–963.
Ozdemir E, St John LS, Gillespie G, Rowland-Jones S, Champlin RE, Molldrem JJ et al. Cytomegalovirus reactivation following allogeneic stem cell transplantation is associated with the presence of dysfunctional antigen-specific CD8+ T cells. Blood 2002; 100: 3690–3697.
Benz C, Utermohlen O, Wulf A, Villmow B, Dries V, Goeser T et al. Activated virus-specific T cells are early indicators of anti-CMV immune reactions in liver transplant patients. Gastroenterology 2002; 122: 1201–1215.
Gratama JW, van Esser JW, Lamers CH, Tournay C, Lowenberg B, Bolhuis RL et al. Tetramer-based quantification of cytomegalovirus (CMV)-specific CD8+ T lymphocytes in T-cell-depleted stem cell grafts and after transplantation may identify patients at risk for progressive CMV infection. Blood 2001; 98: 1358–1364.
Hassan-Walker AF, Vargas Cuero AL, Mattes FM, Klenerman P, Lechner F, Burroughs AK et al. CD8+ cytotoxic lymphocyte responses against cytomegalovirus after liver transplantation: correlation with time from transplant to receipt of tacrolimus. J Infect Dis 2001; 183: 835–843.
Singhal S, Shaw JC, Ainsworth J, Hathaway M, Gillespie GM, Paris H et al. Direct visualization and quantitation of cytomegalovirus-specific CD8+ cytotoxic T-lymphocytes in liver transplant patients. Transplantation 2000; 69: 2251–2259.
Concannon P, Robinson MA . Human T-cell receptor gene nomenclature. Ann NY Acad Sci 1995; 756: 124–129.
Acknowledgements
This work was supported by grants from Ministry of Education, Science, Sports and Culture of Japan (08670508, 10670932, and 14570960); Yamashita Taro-Kensho Memorial Foundation; Uehara Memorial Foundation.
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Saitoh, H., Hirokawa, M., Fujishima, N. et al. The presence and longevity of peripherally expanded donor-derived TCRαβ+ mature T lymphocyte clones after allogeneic bone marrow transplantation for adult myeloid leukemias. Leukemia 17, 1626–1635 (2003). https://doi.org/10.1038/sj.leu.2402994
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.leu.2402994