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Human γδ T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection

Nature Immunology volume 18, pages 393–401 (2017)Cite this article

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Abstract

To investigate how the human γδ T cell pool is shaped during ontogeny and how it is regenerated after transplantation of hematopoietic stem cells (HSCs), we applied an RNA-based next-generation sequencing approach to monitor the dynamics of the repertoires of γδ T cell antigen receptors (TCRs) before and after transplantation in a prospective cohort study. We found that repertoires of rearranged genes encoding γδ TCRs (TRG and TRD) in the peripheral blood of healthy adults were stable over time. Although a large fraction of human TRG repertoires consisted of public sequences, the TRD repertoires were private. In patients undergoing HSC transplantation, γδ T cells were quickly reconstituted; however, they had profoundly altered TCR repertoires. Notably, the clonal proliferation of individual virus-reactive γδ TCR sequences in patients with reactivation of cytomegalovirus revealed strong evidence for adaptive anti-viral γδ T cell immune responses.

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Figure 1: Human γδ TCR repertoires contain highly proliferated oligoclonal sequences.
Figure 2: TRG versus TRD: TCRγ is public and TCRδ is private.
Figure 3: γδ TCR repertoires are stable over time.
Figure 4: Reconstitution of various γδ TCR repertoires after alloHSCT.
Figure 5: Reactivation of CMV induces the proliferation of potential CMV-reactive clones.
Figure 6: Single-cell analysis identifies proliferated γδ T cell clones.

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  • 14 February 2018

    In the version of this Article originally published, in Acknowledgments section "Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R12/29 to C.K. and I.P.)", text were missing. The text has been included in PDF and XML. These have been corrected after print.

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Acknowledgements

We thank E. Hage and T. Schulz for assistance from the central project Z1, an NGS core facility of Collaborative Research Centre SFB900; C. Struckmann and M. Ballmaier for technical guidance and single-cell sorting; the Hannover Unified Biobank of Hannover Medical School; A. Krueger for reading and criticizing the manuscript; and J. Blume for help in cord-blood preparation. Supported by Deutsche Forschungsgemeinschaft, (SFB900/B8 to C.K. and I.P.), Deutsche José Carreras Leukämie-Stiftung e.V. (DJCLS R12/29 to C.K. and I.P.) and PR727/4-1 to I.P.) and the German Federal Ministry of Education and Research (01EO1302 to C.S.-F., C.K. and I.P.).

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Author notes

  1. Christian Koenecke and Immo Prinz: These authors contributed equally to this work.

Authors and Affiliations

  1. Institute of Immunology, Hannover Medical School, Hannover, Germany

    Sarina Ravens, Christian Schultze-Florey, Solaiman Raha, Inga Sandrock, Linda Oberdörfer, Annika Reinhardt, Inga Ravens, Maleen Beck, Reinhold Förster, Christian Koenecke & Immo Prinz

  2. Department of Hematology, Hemostasis, Oncology and Stem Cell Transplantation, Hannover Medical School, Hannover, Germany

    Christian Schultze-Florey, Melanie Drenker, Maleen Beck, Michael Heuser, Felicitas Thol, Arnold Ganser & Christian Koenecke

  3. Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany

    Christian Schultze-Florey, Christian Koenecke & Immo Prinz

  4. Genome Analytics, Helmholtz Centre for Infection Research, Braunschweig, Germany

    Robert Geffers

  5. Department Obstetrics, Gynecology and Reproductive Medicine, Hannover Medical School, Hannover, Germany

    Constantin von Kaisenberg

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Contributions

Sa.R. wrote the manuscript; Sa.R., C.S.-F. and So.R. designed and performed experiments, discussed and analyzed data; I.S., A.R., I.R. and M.B. helped with performing experiments and data analysis; M.D. and L.O. organized, acquired and processed clinical samples; R.G., M.H. and F.T. helped supervise NGS; C.v.K. and A.G. helped supervise clinical sample acquisition; R.F. helped supervise research; C.K. supervised research and the clinical study, and discussed and analyzed data; and I.P. supervised research, discussed and analyzed data and wrote the manuscript.

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Correspondence to Immo Prinz.

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Integrated supplementary information

Supplementary Figure 1 NGS strategy for human γδ TCR repertoires.

(a) NGS strategy to analyze human TRG and TRD repertoires. Amplicons were generated from sorted γδ T cells by mRNA/cDNA based multiplex PCR technology. Multiplex primer sets target Vγ or Vδ and constant gene segments to amplify CDR3 regions followed by Illumina MiSeq sequencing. Illumina sequencing adapters are added as overhangs (red). Obtained sequences were annotated by IMGT as described in the online methods section before downstream bioinformatics analysis. (b) Validation of reproducibility. PBMCs of the same person were isolated and independently processed for NGS. Dot plots represent clonotype frequencies of multiplex PCR replica. (c) Validation of multiplex PCR. PBMCs of the same person were isolated and independently processed for either multiplex (y-axis) or 5’RACE-based (x-axis) amplicon generation strategies.

Supplementary Figure 2 Human γδ TCR repertoires are highly diverse.

(a) Graphs demonstrate numbers and median of abundant clones with a frequency of > 1% within each adult healthy control and cord blood sample of TRG and TRD repertoires. (b) Average frequencies and median of abundant clones (>1%) was determined for each healthy control and cord blood sample. (c) Shannon indices were calculated for TRG and TRD repertoires of healthy adult controls, patients and cord blood. For direct comparison, samples were normalized to 20,000 random productive rearrangements. Horizontal lines display medians. Statistical analysis was performed by paired t test (for TRG and TRD repertoire comparisons) and one-way ANOVA (between unrelated samples). * p ≤ 0.1; ** p ≤ 0.01; *** p ≤ 0.001; **** p < 0.0001. (d) Vγ9+ and Vγ9− TRG as well as Vδ2+ and Vδ1+ TRD repertoires were separately analyzed to calculate Shannon diversity indices of all healthy controls and cord blood samples. Samples were normalized to 2000 random productive reads.

Supplementary Figure 3 Quick reconstitution of γδ T cells after alloHSCT.

(a,b) Graphs show total numbers of (a) total gd T cells or (b) Vγ9+ cells per μl blood of healthy adult controls and patients before and up to 180 days after alloHSCT as determined by flow cytometry. Horizontal lines represent median values.

Supplementary Figure 4 Dynamics of the gd TCR repertoire in alloHSCT patients without and with reactivation of CMV.

(a,b) Stacked area graphs illustrate proportions of Top20 clones before and after alloHSCT in (a) four patients without and (b) four patients with CMV reactivation, while all other non-Top20 clones are summarized in light grey (related to Fig. 4a,b and 5a,b of the main manuscript). Expanded Top20 Vγ9+ and Vδ2+ sequences are highlighted in blue colors, Vγ9− and Vδ2− sequences are highlighted in orange colors. The day of transplantation (Tx) was set to zero to reflect T cell depletion, but no blood was drawn at Tx. Sequences appearing in the Top20 before, but not after Tx, are coded in gray shades. Arrows in (b) indicate the day of CMV-reactivation. Indicated pre-transplant repertoires could not be determined (nd) due to sample quality.

Supplementary Figure 5 Development of gd TCR repertoires after alloHSCT.

(a) NGS analysis of patients without CMV reactivation before and after alloHSCT. Box plots display median and range of Vγ2, Vγ3, Vγ4, Vγ5, Vγ8 and Vγ9 as well as Vγ1, Vδ2, Vδ3 and Vδ5 chains. (b) Shannon diversity calculation of all TRG and TRD repertoires from patients before and up to 180 days after alloHSCT. Samples were randomly sampled to 20,000 productive rearrangements. Vertical lines show medians. (c) TRG repertoires of all cord blood, healthy controls and patients before and up to 180 days after alloHSCT were separated into Vγ9+ clones to calculate frequencies of Vγ9JP+ clones. Horizontal lines represent median values.

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Ravens, S., Schultze-Florey, C., Raha, S. et al. Human γδ T cells are quickly reconstituted after stem-cell transplantation and show adaptive clonal expansion in response to viral infection. Nat Immunol 18, 393–401 (2017). https://doi.org/10.1038/ni.3686

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