Skip to main content

Advertisement

SpringerLink
Log in

CDR3 and V genes show distinct reconstitution patterns in T cell repertoire post-allogeneic bone marrow transplantation

  • Original Article
  • Published:
Immunogenetics Aims and scope Submit manuscript

Abstract

Restoration of T cell repertoire diversity after allogeneic bone marrow transplantation (allo-BMT) is crucial for immune recovery. T cell diversity is produced by rearrangements of germline gene segments (V (D) and J) of the T cell receptor (TCR) α and β chains, and selection induced by binding of TCRs to MHC-peptide complexes. Multiple measures were proposed for this diversity. We here focus on the V-gene usage and the CDR3 sequences of the beta chain. We compared multiple T cell repertoires to follow T cell repertoire changes post-allo-BMT in HLA-matched related donor and recipient pairs. Our analyses of the differences between donor and recipient complementarity determining region 3 (CDR3) beta composition and V-gene profile show that the CDR3 sequence composition does not change during restoration, implying its dependence on the HLA typing. In contrast, V-gene usage followed a time-dependent pattern, initially following the donor profile and then shifting back to the recipients' profile. The final long-term repertoire was more similar to that of the recipient's original one than the donor’s; some recipients converged within months, while others took multiple years. Based on the results of our analyses, we propose that donor-recipient V-gene distribution differences may serve as clinical biomarkers for monitoring immune recovery.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

Data Availability

The datasets generated and/or analyzed during the current study are available in the Adaptive Biotechnologies database (Seattle, WA; https://clients.adaptivebiotech.com).

References

  • Bassing CH, Swat W, Alt FW (2002) The mechanism and regulation of chromosomal V ( D ) J Recombination. Cell 109:45–55

    Google Scholar 

  • Benichou J, Ben-Hamo R, Louzoun Y, Efroni S (2011) Rep-Seq : uncovering the immunological repertoire through next-generation sequencing. Immunology 135(3):183–191

    Google Scholar 

  • Benichou JIC, van Heijst JWJ, Glanville J, Louzoun Y (2017) Converging evolution leads to near maximal junction diversity through parallel mechanisms in B and T cell receptors. Phys Biol 14(4):5003

    Google Scholar 

  • Benjamini Y, Drai D, Elmer G, Kafkafi N, Golani I (2001) Controlling the false discovery rate in behavior genetics research. Behav Brain Res 125(1–2):279–284

    CAS  PubMed  Google Scholar 

  • Borg I, Groenen P (2005) Modern Multidimensional Scaling: theory and applications, 2nd edn. Springer-Verlag, New York, pp 207–212

    Google Scholar 

  • Britanova OV, Putintseva EV, Shugay M, Merzlyak EM, Turchaninova MA, Staroverov DB, Bolotin DA, Lukyanov S, Bogdanova EA, Mamedov IZ, Lebedev YB, Chudakov DM (2014) Age-related decrease in TCR repertoire diversity measured with deep and normalized sequence profiling. J Immunol 192(6):2689–2698

    CAS  PubMed  Google Scholar 

  • Buhler S, Bettens F, Dantin C, Ferrari-Lacraz S, Ansari M, Mamez AC, Masouridi-Levrat S, Chalandon Y, Villard J (2019) Genetic T-cell receptor diversity at 1 year following allogeneic hematopoietic stem cell transplantation. Leukemia 34(5):1422–1432

    PubMed  Google Scholar 

  • Burrows SR, Silins SL, Moss DJ, Khanna R, Misko IS, Argaet VP (1995) T cell receptor repertoire for a viral epitope in humans is diversified by tolerance to a background major histocompatibility complex antigen. J Exp Med 182(6):1703–1715

    CAS  PubMed  Google Scholar 

  • Cells HCDT, Luo W, Ma L, Wen Q, Zhou M, Wang X (2009) Analysis of the conservation of T cell receptor alpha and beta chain variable regions gene in pp65 peptide-specific (2):105–110

  • Chaudhry MS, Velardi E, Malard F, Van Den Brink MRM (2019) Immune reconstitution after allogeneic hematopoietic stem cell transplantation: time to T up the thymus. J Immunology 198:40–46

    Google Scholar 

  • Cieri N, Oliveira G, Greco R, Forcato M, Taccioli C, Cianciotti B, Valtolina V, Noviello M, Vago L, Bondanza A, Lunghi F, Marktel S, Bellio L, Bordignon C, Bicciato S, Peccatori J, Ciceri F, Bonini C (2015) Generation of human memory stem T cells after haploidentical T-replete hematopoietic stem cell transplantation. Blood 125(18):2865–2874

    CAS  PubMed  Google Scholar 

  • Dean J, Emerson RO, Vignali M, Sherwood AM, Rieder MJ, Carlson CS, Robins HS (2015) Annotation of pseudogenic gene segments by massively parallel sequencing of rearranged lymphocyte receptor loci. Genome Medicine 123(7):1–8

    Google Scholar 

  • Dickinson AM (2016) Immune reconstitution after allogeneic hematopoietic stem cell transplantation. Front Immunol 17(7):507

    Google Scholar 

  • Douek DC, Vescio RA, Betts MR, Brenchley JM, Hill BJ, Zhang L, Berenson JR, Collins RH, Koup RA (2000) Assessment of thymic output in adults after haematopoietic stem-cell transplantation and prediction of T-cell reconstitution. Lancet 355:1875–1881

    CAS  PubMed  Google Scholar 

  • Elhanati Y, Sethna Z, Callan CG, Mora T, Walczak AM (2018) Predicting the spectrum of TCR repertoire sharing with a data-driven model of recombination. Immunol Rev 284(1):167–179

    CAS  PubMed  PubMed Central  Google Scholar 

  • Fallen PR, Mcgreavey L, Madrigal JA, Potter M, Ethell M, Prentice HG, Travers PJ (2003) Lymphoid reconstitution factors affecting reconstitution of the T cell compartment in allogeneic haematopoietic cell transplant recipients. Bone Marrow Transplant 32(10):1001–1014

    CAS  PubMed  Google Scholar 

  • Gauthier S, Moutuou MM, Daudelin F, Leboeuf D, Guimond M (2018) IL-7 is the limiting homeostatic factor that constrains homeostatic proliferation of CD8 + T cells after allogeneic stem cell transplantation and graft-versus-host disease. Biol Blood Marrow Transplant 25(4):648–655

    PubMed  Google Scholar 

  • Gerlinger M, Quezada SA, Peggs KS, Furness AJ, Fisher R, Marafioti T, Swanton C (2013) Ultra-deep T cell receptor sequencing reveals the complexity and intratumour heterogeneity of T cell clones in renal cell carcinomas. J Pathol 231(4):424–432

    CAS  PubMed  PubMed Central  Google Scholar 

  • Heather JM, Ismail M, Oakes T, Chain B (2018) High-throughput sequencing of the T-cell receptor repertoire: pitfalls and opportunities. Brief Bioinform 19(4):554–565

    CAS  PubMed  Google Scholar 

  • Izraelson M, Nakonechnaya TO, Moltedo B, Egorov ES, Kasatskaya SA, Putintseva EV, Mamedov IZ, Staroverov DB, Shemiakina II, Zakharova MY, Davydov AN, Bolotin DA, Shugay M, Chudakov DM, Rudensky AY, Britanova OV (2018) Comparative analysis of murine T-cell receptor repertoires. Immunology 153(2):133–144

    CAS  PubMed  Google Scholar 

  • Johnson SC (1967) Hierarchical clustering schemes. Psychometrika 32:241–254

    CAS  PubMed  Google Scholar 

  • Kanakry CG, Coffey DG, Towlerton AM, Vulic A, Storer BE, Chou J, Yeung CC, Gocke CD, Robins HS, O’Donnell PV, Luznik L, Warren EH (2016) Origin and evolution of the T cell repertoire after posttransplantation cyclophosphamide. JCI Insight 1(5):e86252

    PubMed  PubMed Central  Google Scholar 

  • Kanakry CG, O'Donnell PV, Furlong T, de Lima MJ, Wei W, Medeot M, Mielcarek M, Champlin RE, Jones RJ, Thall PF, Andersson BS, Luznik L (2014) Multi-institutional study of post-transplantation cyclophosphamide as single-agent graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation using myeloablative busulfan and fludarabine conditioning. J Clin Oncol 32(31):3497–3505

  • Koning D, Costa AI, Hoof I, Miles JJ, Nanlohy NM, Ladell K, Matthews KK, Venturi V, Schellens IM, Borghans JA, Kesmir C, Price DA, van Baarle D (2012) CD8+ TCR repertoire formation is guided primarily by the peptide component of the antigenic complex. J Immunol 190(3):931–939

    PubMed  Google Scholar 

  • Koning CD, Nierkens S, Boelens JJ (2016) Strategies before, during, and after hematopoietic cell transplantation to improve T-cell immune reconstitution. Blood 128(23):2607–2616

    PubMed  Google Scholar 

  • Krenger W, Blazar BR, Holla GA (2011) Thymic T-cell development in allogeneic stem cell transplantation. Blood 117(25):6768–6777

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kullback S, Leibler RA (1951) On Information and Sufficiency. Ann Math Stat 22(1):79–86

    Google Scholar 

  • Levenshtein VI (1966) Binary codes capable of correcting deletions, insertions, and reversals. Sov Phys Dokl 10(8):707–710

    Google Scholar 

  • Lissina A, Chakrabarti LA, Takiguchi M, Appay V (2016) TCR clonotypes: molecular determinants of T-cell efficacy against HIV. Curr Opin Virol 16:77–85. https://doi.org/10.1016/j.coviro.2016.01.017

    Article  CAS  PubMed  Google Scholar 

  • Lynch HE, Goldberg GL, Chidgey A, Van Den Brink MRM, Boyd R, Sempowski GD (2009) Thymic involution and immune reconstitution. Cell 30(7):366–373. https://doi.org/10.1016/j.it.2009.04.003

    Article  CAS  Google Scholar 

  • Madi A, Shifrut E, Reich-Zeliger S, Gal H, Best K, Ndifon W, Chain B, Cohen IR, Friedman N (2014) T-cell receptor repertoires share a restricted set of public and abundant CDR3 sequences that are associated with self-related immunity. Genome Res 24(10):1603–1612

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mamedov IZ, Britanova OV, Bolotin DA, Chkalina AV, Staroverov DB, Zvyagin IV, Kotlobay AA, Turchaninova MA, Fedorenko DA, Novik AA, Sharonov GV, Lukyanov S, Chudakov DM, Lebedev YB (2011) Quantitative tracking of T cell clones after haematopoietic stem cell transplantation. EMBO Mol Med 3(4):201–207

    CAS  PubMed  PubMed Central  Google Scholar 

  • Meier JA, Haque M, Fawaz M, Abdeen H, Coffey D, Towlerton A, Abdeen A, Toor A, Warren E, Reed J, Kanakry CG, Keating A, Luznik L, Toor AA (2019) Biology of blood and T cell repertoire evolution after allogeneic bone marrow transplantation: an organizational perspective. Biol Blood Marrow Transplant 25(5):868–882

    PubMed  PubMed Central  Google Scholar 

  • Muraro PA, Robins H, Malhotra S, Howell M, Phippard D, Desmarais C, de Paula Alves Sousa A, Griffith LM, Lim N, Nash RA, Turka LA, (2014) T cell repertoire following autologous stem cell transplantation for multiple sclerosis. J Clin Invest 124(3):1168–1172

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakano N (1991) T cell receptor V gene usage of islet beta cell-reactive T cells is not restricted in non-obese diabetic mice. J Exp Med 173(5):1091–1097

    CAS  PubMed  Google Scholar 

  • Nakasone H, Tanaka Y, Yamazaki R, Terasako K, Sato M, Sakamoto K, Kanda Y (2014) Single-cell T-cell receptor-β analysis of HLA-A*2402-restricted CMV- pp65-specific cytotoxic T-cells in allogeneic hematopoietic SCT. Bone Marrow Transplant 49(1):87–94

    CAS  PubMed  Google Scholar 

  • Navarro G (2001) A guided tour to approximate string matching. ACM Comput Surv 33(1):31–88

    Google Scholar 

  • Ogonek J, Kralj Juric M, Ghimire S, Varanasi PR, Holler E, Greinix H, Weissinger E (2016) Immune reconstitution after allogeneic hematopoietic stem cell transplantation. Front Immunol 17(7):507

    Google Scholar 

  • Pogorelyy MV, Fedorova AD, McLaren JE, Ladell K, Bagaev DV, Eliseev AV, Mikelov AI, Koneva AE, Zvyagin IV, Price DA, Chudakov DM, Shugay M (2018) Exploring the pre-immune landscape of antigen-specific T Cells. Genome Medicine 10(1):68–82

    PubMed  PubMed Central  Google Scholar 

  • Ringhoffer S, Rojewski M, Döhner H, Bunjes D, Ringhoffer M (2013) T-cell reconstitution after allogeneic stem cell transplantation : assessment by measurement of the sjTREC / β TREC ratio and thymic naïve T cells. Haematologica 98(10):1600–1608

    CAS  PubMed  PubMed Central  Google Scholar 

  • Robins H (2010) Overlap and effective size of the human CD8+ T-cell receptor repertoire. Sci Transl Med 2(47):1–9

    Google Scholar 

  • Robinson TM, O’Donnell PV, Fuchs EJ, Luznik L (2016) Haploidentical bone marrow and stem cell transplantation: experience with post-transplantation cyclophosphamide. Semin Hematol 53(2):90–97

    PubMed  PubMed Central  Google Scholar 

  • Rubelt F, Bolen CR, Mcguire HM, Heiden JA, Vander GMD, Levin M, Davis MM (2016) Individual heritable differences result in unique cell lymphocyte receptor repertoires of naïve and antigen-experienced cells. Nat Commun 6:1–12

  • Sakai R, Kinouchi T, Kawamoto S, Dana MR, Hamamoto T, Tsuru T, Yamagami S (2002) Construction of human corneal endothelial cDNA library and identification of novel active genes. Invest Ophthalmol Vis Sci 43(6):1749–1756

    PubMed  Google Scholar 

  • Scheckelhoff MR, Deepe GS (2006) Pulmonary V beta 4+ T cells from Histoplasma capsulatum-infected mice respond to a homologue of Sec31 that confers a protective response. J Infect Dis 193(6):888–897

    CAS  PubMed  PubMed Central  Google Scholar 

  • Schrama D, Ritter C, Becker JC (2017) T cell receptor repertoire usage in cancer as a surrogate marker for immune responses. Seminars in ImmunopathologyImmunopathol 39:255–268

  • Shugay M, Bolotin DA, Putintseva EV, Pogorelyy MV, Mamedov IZ, Chudakov DM (2013) Huge overlap of individual TCR beta repertoires. Front Immunol 4:466

    PubMed  PubMed Central  Google Scholar 

  • Toubert A, Glauzy S, Douay C, Clave E (2012) Thymus and immune reconstitution after allogeneic hematopoietic stem cell transplantation in humans: never say. Tissue Antigens 79(2):83–89

    CAS  PubMed  Google Scholar 

  • Turner SJ, Kedzierska K, La Gruta NL, Webby R, Doherty PC (2004) Characterization of CD8+ T cell repertoire diversity and persistence in the influenza a virus model of localized, transient infection. Semin Immunol 16(3):179–184

    CAS  PubMed  Google Scholar 

  • Yew PY, Alachkar H, Yamaguchi R, Kiyotani K, Fang H, Yap KL, Liu HT, Wickrema A, Artz A, van Besien K, Imoto S, Miyano S, Bishop MR, Stock W, Nakamura Y (2015) Quantitative characterization of T-cell repertoire in allogeneic hematopoietic stem cell transplant recipients. Bone Marrow Transplant 50(9):1227–1234

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zvyagin IV, Pogorelyy MV, Ivanova ME, Komech EA, Shugay M, Bolotin DA, Shelenkov AA, Kurnosov AA, Staroverov DB, Chudakov DM, Lebedev YB, Mamedov IZ (2014) Distinctive properties of identical twins TCR repertoires revealed by high-throughput sequencing. Proc Natl Acad Sci U S A 111(16):5980–5985

    CAS  PubMed  PubMed Central  Google Scholar 

Download references

Author information

Author notes

  1. Nili Tickotsky-Moskovitz and Shirit Dvorkin equally contributed on this work.

Authors and Affiliations

  1. The Goodman Faculty of Life Sciences, Bar Ilan University, Ramat Gan, Israel

    Nili Tickotsky-Moskovitz & Sol Efroni

  2. Department of Mathematics, Bar Ilan University, Ramat Gan, Israel

    Yoram Louzoun & Shirit Dvorkin

  3. Azrieli Faculty of Medicine, Bar-Ilan University, Safed, Israel

    Adi Rotkopf & Amir Asher Kuperman

  4. Blood Coagulation Service and Pediatric Hematology Clinic, Galilee Medical Center, Nahariya, Israel

    Amir Asher Kuperman

Authors
  1. Nili Tickotsky-Moskovitz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yoram Louzoun
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shirit Dvorkin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Adi Rotkopf
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Amir Asher Kuperman
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sol Efroni
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

SD designed the formalism and implemented it; NTM collected the data and wrote the manuscript; AR and AAK collected the data and prepared it; SE supervised the work; YL supervised the work and wrote the manuscript.

Corresponding author

Correspondence to Yoram Louzoun.

Ethics declarations

Conflict of interests

The authors declare that they have no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 1578 KB)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Tickotsky-Moskovitz, N., Louzoun, Y., Dvorkin, S. et al. CDR3 and V genes show distinct reconstitution patterns in T cell repertoire post-allogeneic bone marrow transplantation. Immunogenetics 73, 163–173 (2021). https://doi.org/10.1007/s00251-020-01200-7

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00251-020-01200-7

Keywords

Search

Navigation