Publications by authors named "Reetta Vanhanen"

8 Publications

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Characterization of human T cell receptor repertoire data in eight thymus samples and four related blood samples.

Data Brief 2021 Apr 20;35:106751. Epub 2021 Jan 20.

Research Programs Unit, Translational Immunology, University of Helsinki, Haartmaninkatu 3, 00290 Helsinki, Finland.

T cell receptor (TCR) is a heterodimer consisting of TCRα and TCRβ chains that are generated by somatic recombination of multiple gene segments. Nascent TCR repertoire undergoes thymic selections where non-functional and potentially autoreactive receptors are removed. During the last years, the development of high-throughput sequencing technology has allowed a large scale assessment of TCR repertoire and multiple analysis tools are now also available. In our recent manuscript, [1], we show highly overlapping thymic TCR repertoires in unrelated individuals. In the current Data in Brief article, we provide a more detailed characterization of the basic features of these thymic and related peripheral blood TCR repertoires. The thymus samples were collected from eight infants undergoing corrective cardiac surgery, two of whom were monozygous twins [2]. In parallel with the surgery, a small aliquot of peripheral blood was drawn from four of the donors. Genomic DNA was extracted from mechanically released thymocytes and circulating leukocytes. The sequencing of TCRα and TCRβ repertoires was performed at ImmunoSEQ platform (Adaptive Biotechnologies). The obtained repertoire data were analysed applying relevant features from immunoSEQ® 3.0 Analyzer (Adaptive Biotechnologies) and a freely available VDJTools software package for programming language R [3]. The current data analysis displays the basic features of the sequenced repertoires including observed TCR diversity, various descriptive TCR diversity measures, and V and J gene usage. In addition, multiple methods to calculate repertoire overlap between two individuals are applied. The raw sequence data provide a large database of reference TCRs in healthy individuals at an early developmental stage. The data can be exploited to improve existing computational models on TCR repertoire behaviour as well as in the generation of new models.
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http://dx.doi.org/10.1016/j.dib.2021.106751DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7859292PMC
April 2021

Human thymic T cell repertoire is imprinted with strong convergence to shared sequences.

Mol Immunol 2020 11 19;127:112-123. Epub 2020 Sep 19.

Research Programs Unit, Translational Immunology and Medicum, Department of Bacteriology and Immunology, University of Helsinki. Haartmaninkatu 3, 00290 Helsinki, Finland. Electronic address:

A highly diverse repertoire of T cell antigen receptors (TCR) is created in the thymus by recombination of gene segments and the insertion or deletion of nucleotides at the junctions. Using next-generation TCR sequencing we define here the features of recombination and selection in the human TCRα and TCRβ locus, and show that a strikingly high proportion of the repertoire is shared by unrelated individuals. The thymic TCRα nucleotide repertoire was more diverse than TCRβ, with 4.1 × 10 vs. 0.81 × 10 unique clonotypes, and contained nonproductive clonotypes at a higher frequency (69.2% vs. 21.2%). The convergence of distinct nucleotide clonotypes to the same amino acid sequences was higher in TCRα than in TCRβ repertoire (1.45 vs. 1.06 nucleotide sequences per amino acid sequence in thymus). The gene segment usage was biased, and generally all individuals favored the same genes in both TCRα and TCRβ loci. Despite the high diversity, a large fraction of the repertoire was found in more than one donor. The shared fraction was bigger in TCRα than TCRβ repertoire, and more common in in-frame sequences than in nonproductive sequences. Thus, both biases in rearrangement and thymic selection are likely to contribute to the generation of shared repertoire in humans.
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http://dx.doi.org/10.1016/j.molimm.2020.09.003DOI Listing
November 2020

Identifying the inheritable component of human thymic T cell repertoire generation in monozygous twins.

Eur J Immunol 2020 05 14;50(5):748-751. Epub 2020 Jan 14.

Research Programs Unit, Translational Immunology, University of Helsinki, Helsinki, Finland.

We have analyzed T cell receptor repertoires in a unique set of thymus samples from a pair of monozygotic twins. While genetics affect the V(D)J rearrangement and generation of junctional sequences, the thymic selections seem largely stochastic and import no detectable inheritable effect at clonal level.
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http://dx.doi.org/10.1002/eji.201948404DOI Listing
May 2020

Epigenetic and transcriptional analysis supports human regulatory T cell commitment at the CD4+CD8+ thymocyte stage.

Cell Immunol 2020 01 11;347:104026. Epub 2019 Dec 11.

Translational Immunology Research Program, University of Helsinki, 00014 Helsinki, Finland; Medicum, University of Helsinki, 00014 Helsinki, Finland.

The natural CD25+ FOXP3+ regulatory T cell (Treg) population is generated as a distinct lineage in the thymus, but the details of Treg development in humans remain unclear, and the timing of Treg commitment is also contested. Here we have analyzed the emergence of CD25+ cells at the CD4+CD8+ double positive (DP) stage in the human thymus. We show that these cells share T cell receptor repertoire with CD25+ CD4 single-positive thymocytes, believed to be committed Tregs. They already have a fully demethylated FOXP3 enhancer region and thus display stable expression of FOXP3 and the associated Treg phenotype. Transcriptome analysis also grouped the DP CD25+ and CD4 CD25+ thymocytes apart from the CD25- subsets. Together with earlier studies, our data are consistent with human Treg commitment already at the DP thymocyte stage. We suggest that the most important antigens and signals necessary for human Treg differentiation may be found in the thymic cortex.
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http://dx.doi.org/10.1016/j.cellimm.2019.104026DOI Listing
January 2020

Common gamma chain cytokines promote regulatory T cell development and survival at the CD4 CD8 stage in the human thymus.

Scand J Immunol 2018 Jun 15:e12681. Epub 2018 Jun 15.

Haartman Institute, Department of Bacteriology and Immunology and, Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland.

Thymic commitment of human FOXP3 regulatory T cells begins at the double positive (DP) CD4 CD8 stage. In the current study we show that interleukin-2 promotes the development of FOXP3 thymocytes and enhances their survival at the DP phase. IL-2 increases the frequency of FOXP3 cells and promotes the Treg phenotype after TCR-mediated positive selection at the most mature DP stage. However, it has no effect on FOXP3 cells at the earlier maturation steps before positive selection. DP FOXP3 are highly susceptible to cell death but IL-2 promotes their survival. The anti-apoptotic protein BCL-2 (B Cell Lymphoma 2) is also upregulated by IL-2 at the most mature DP stage. In addition to IL-2, we identify IL-15 to have a significant role in the upregulating FOXP3 and survival of Tregs at the DP phase. IL-7 also increases the expression of BCL-2 in the DP FOXP3 thymocytes. Our results indicate that common gamma chain cytokines IL-2, IL-7 and IL-15 promote the development of regulatory T cells at the most mature DP stage after TCR-mediated positive selection through suppressing cell death. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1111/sji.12681DOI Listing
June 2018

T cell receptor diversity in the human thymus.

Mol Immunol 2016 08 19;76:116-22. Epub 2016 Jul 19.

Medicum, Department of Bacteriology and Immunology and Research Programs Unit, Immunobiology, University of Helsinki, 00014 Helsinki, Finland.

A diverse T cell receptor (TCR) repertoire is essential for adaptive immune responses and is generated by somatic recombination of TCRα and TCRβ gene segments in the thymus. Previous estimates of the total TCR diversity have studied the circulating mature repertoire, identifying 1 to 3×10(6) unique TCRβ and 0.5×10(6) TCRα sequences. Here we provide the first estimate of the total TCR diversity generated in the human thymus, an organ which in principle can be sampled in its entirety. High-throughput sequencing of samples from four pediatric donors detected up to 10.3×10(6) unique TCRβ sequences and 3.7×10(6) TCRα sequences, the highest directly observed diversity so far for either chain. To obtain an estimate of the total diversity we then used three different estimators, preseq and DivE, which measure the saturation of rarefaction curves, and Chao2, which measures the size of the overlap between samples. Our results provide an estimate of a thymic repertoire consisting of 40 to 70×10(6) unique TCRβ sequences and 60 to 100×10(6) TCRα sequences. The thymic repertoire is thus extremely diverse. Moreover, extrapolation of the data and comparison with earlier estimates of peripheral diversity also suggest that the thymic repertoire is transient, with different clones produced at different times.
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http://dx.doi.org/10.1016/j.molimm.2016.07.002DOI Listing
August 2016

Interleukin-7 promotes human regulatory T cell development at the CD4+CD8+ double-positive thymocyte stage.

J Leukoc Biol 2016 09 10;100(3):491-8. Epub 2016 Mar 10.

Haartman Institute, Department of Bacteriology and Immunology, and Research Programs Unit, Immunobiology, University of Helsinki, Helsinki, Finland; and.

Although mature human FOXP3(+) regulatory T cells are CD127 (IL-7Rα) negative, CD4(+)CD8(+) FOXP3(+) thymocytes express relatively high levels of CD127 and are responsive to IL-7. However, the role of IL-7 in human regulatory T cell development is poorly known. We show that at the CD4(+)CD8(+) stage, FOXP3(+) thymocytes are highly susceptible to apoptosis, and IL-7 selectively rescues them from death, leading to an increased frequency of FOXP3(+) cells. IL-7 also promotes the development of regulatory T cell phenotype by inducing up-regulation of FOXP3(+) and CTLA-4 expression. In contrast, IL-7 does not enhance proliferation of FOXP3(+)thymocytes or induce demethylation of FOXP3(+) regulatory T cell-specific demethylated region. After the CD4(+)CD8(+) stage, the FOXP3(+) thymocytes down-regulate CD127 expression but despite very low levels of CD127, remain responsive to IL-7. These results suggest that IL-7 affects human regulatory T cell development in the thymus by at least 2 distinct mechanisms: suppression of apoptosis and up-regulation of FOXP3(+) expression.
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http://dx.doi.org/10.1189/jlb.1A0415-164RDOI Listing
September 2016
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