Fractal Organization of the Human T Cell Repertoire in Health and after Stem Cell Transplantation

Meier, Jeremy A.; Roberts, Catherine C.; Avent, Kassi; Hazlett, Allison F.; Berrie, Jennifer; Payne, Kyle K.; Hamm, David; Desmarais, Cindy; Sanders, Catherine; Hogan, Kevin T.; Archer, Kellie J.; Manjili, Masoud H.; Toor, Amir A.

doi:10.1016/j.bbmt.2012.12.004

Cited by 54 publications

(85 citation statements)

References 25 publications

(28 reference statements)

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“…As previously described, CD3þ cells were isolated from SCT donor samples and cDNA synthesized from these cells [10]. The cDNA was then sent to Adaptive Biotechnologies (Seattle, WA) for high-throughput sequencing of the TCR b CDR3 region using the ImmunoSEQ assay.…”

Section: T-cell Clonal Frequencymentioning

confidence: 99%

“…Repetitive or cyclic phenomenon too may be described mathematically using trigonometric ratios. It is to be noted that the universal constants p and e have a role in calculating the trigonometric ratios and FD, and have been identified in analysis of the T-cell repertoire [10], which would imply that the TCR locus may be arranged in conformity with these constants, and demonstrate self-similarity as well as periodic characteristics. An inspection of the known sequence of the TCR loci with attention to V and J gene segment size and spacing supports this notion.…”

Section: Introductionmentioning

confidence: 99%

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On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments

Toor

Rahmani

et al. 2016

J. R. Soc. Interface.

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We dedicate this work to Mr Omair Ahmed Toor and other people with Down's Syndrome and patients with congenital neurological disorders from around the world, whose constant struggle to overcome the challenges of everyday life and better themselves are an inspiration to all.On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments School of Engineering, Virginia Commonwealth University, Richmond, VA, USAThe human T-cell repertoire is complex and is generated by the rearrangement of variable (V), diversity (D) and joining (J) segments on the T-cell receptor (TCR) loci. The T-cell repertoire demonstrates self-similarity in terms clonal frequencies when defined by V, D and J gene segment usage; therefore to determine whether the structural ordering of these gene segments on the TCR loci contributes to the observed clonal frequencies, the TCR loci were examined for self-similarity and periodicity in terms of gene segment organization. Logarithmic transformation of numeric sequence order demonstrated that the V and J gene segments for both T-cell receptor a (TRA) and b (TRB) loci are arranged in a self-similar manner when the spacing between the adjacent segments was considered as a function of the size of the neighbouring gene segment, with an average fractal dimension of approximately 1.5. Accounting for the gene segments occurring on helical DNA molecules with a logarithmic distribution, sine and cosine functions of the log-transformed angular coordinates of the start and stop nucleotides of successive TCR gene segments showed an ordered progression from the 5 0 to the 3 0 end of the locus, supporting a log-periodic organization. T-cell clonal frequency estimates, based on V and J segment usage, from normal stem cell donors were plotted against the V and J segment on TRB locus and demonstrated a periodic distribution. We hypothesize that this quasi-periodic variation in genesegment representation in the T-cell clonal repertoire may be influenced by the location of the gene segments on the periodic-logarithmically scaled TCR loci. Interactions between the two strands of DNA in the double helix may influence the probability of gene segment usage by means of either constructive or destructive interference resulting from the superposition of the two helices.

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Section: T-cell Clonal Frequencymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments

Toor

Rahmani

et al. 2016

J. R. Soc. Interface.

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“…New technologies, such as next-generation sequencing (NGS), offer the opportunity to assess the TCR repertoire on an unprecedented level. So far, most TCR sequencing in the setting of allogeneic transplantation has focused on assessment of the TCR-b chain [5][6][7]. A recent report assessed the TCR-b repertoire of CMV-specific T cells by NGS and demonstrated a high prevalance of dominant clonotypes in kidney allograft recipients [8].…”

Section: Introductionmentioning

confidence: 99%

Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8+ T cell receptor alpha repertoire following allogeneic transplantation

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Eugster²,

Heidenreich

et al. 2016

Clinical and Experimental Immunology

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SummaryAllogeneic stem cell transplantation is potentially curative, but associated with post-transplantation complications, including cytomegalovirus (CMV) infections. An effective immune response requires T cells recognizing CMV epitopes via their T cell receptors (TCRs). Little is known about the TCR repertoire, in particular the TCR-a repertoire and its clinical relevance in patients following stem cell transplantation. Using next-generation sequencing we examined the TCR-a repertoire of CD8 T cells and half of the total CD8 1 T cell repertoire was dominated by few CMV-reactive clonotypes. Some TCR-a clonotypes were shared between patients. Gene expression of the circulating CMV-specific CD8 1 T cells was consistent with chronically activated effector memory T cells. The CD8 1 T cell response to CMV reactivation resulted in an expansion of a few TCR-a clonotypes to dominate the CD8 1 repertoires. These results warrant further larger studies to define the ability of oligoclonally expanded T cell clones to achieve an effective anti-viral T cell response in this setting.

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“…These results were consistent with previous reports that patients with GVHD after HSCT and stem cell transplant recipients had a significantly smaller and restricted T-cell repertoire. 7,14 We found that there was little similarity among the TRB repertoires of different healthy individuals with Bhattacharyya coefficients <0.10, and there was even less similarity among the TRB repertoires of different patients with GVHD with Bhattacharyya coefficients typically <0.08 (data not shown). The top 100 CDR3 sequences and their V/D/J gene rearrangements in healthy individuals and patients with GVHD are shown in Supplemental Tables S2 and S3.…”

Section: Trb Repertoire By Ngsmentioning

confidence: 79%

“…These results are consistent with previous reports that patients with GVHD after HSCT and stem cell transplant recipients have a significantly smaller and restricted T-cell repertoire. 7,14 NGS technology has emerged as a tool to quantify TCR repertoires that is quickly moving from a research tool to commercial and clinical testing for assessment of clonality and assessment of immune interventions. Defining standards and limitations of library preparation, sequencing and data analysis for detection of TCR repertoires with NGS is a recognized need in the field.…”

Section: à5mentioning

confidence: 99%

Methodologic Considerations in the Application of Next-Generation Sequencing of Human TRB Repertoires for Clinical Use

You

Zheng

et al. 2017

The Journal of Molecular Diagnostics

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Next-generation sequencing (NGS) of immune receptors has become a standard tool to assess minimal residual disease (MRD) in patients treated for lymphoid malignancy, and it is being used to study the T-cell repertoire in many clinical settings. To better understanding the potential clinical utility and limitations of this application outside of MRD, we developed a BIOMED-2 primerebased NGS method and characterized its performance in controls and patients with graft-versus-host disease (GVHD) after allogeneic hematopoietic transplant. For controls and patients with GVHD, replicate sequencing of the same T-cell receptor b (TRB) libraries was highly reproducible. Higher variability was observed in sequencing of different TRB libraries made from the same DNA stock. Variability was increased in patients with GVHD compared with controls; patients with GVHD also had lower diversity than controls. In the T-cell repertoire of a healthy person, approximately 99.6% of the CDR3 clones were in low abundance, with frequency <10À3 . A single library could identify >93% of the clones with frequency !10 À3 in the repertoire. Sequencing in duplicate increased the average detection rate to >97%. This work demonstrates that NGS reliably and robustly characterizes TRB populations in healthy individuals and patients with GVHD with frequency !10 À3 and provides a methodologic framework for applying NGS immune repertoire methods to clinical testing applications beyond MRD. (J Mol Diagn 2017, 19: 72e83; http://dx.doi.org/10.1016/j.jmoldx.2016 Study and analysis of T-cell receptor (TCR) repertoires are essential for better understanding the development and reconstitution of immune systems, for providing insights into the pathogenesis of immune disorders, and for diagnosing and assessing therapeutic interventions for diseases driven by T cells. Next-generation sequencing (NGS) technology has become a standard method for assessing minimal residual disease (MRD) in patients with lymphoid malignancies. From a technical standpoint, MRD is a relatively simple application of NGS technology, essentially looking for known malignant or related somatically mutated clones; by combining replicate libraries, a sensitivity of 1 in 10 À5 has been demonstrated for MRD. Beyond detecting MRD, NGS is also an innovative and promising approach to assess clonal populations of T cells in healthy people during immune system development, patients with suspected malignancy, response to targeted therapies, immune reconstitution in patients undergoing hematopoietic cell transplant, and autoimmune diseases. 7,9e25 However, assessment of the T-cell repertoire in individuals is a far more complex task than assessment of MRD. In consideration of extending NGS methods beyond MRD applications in clinical laboratories, we examined the opportunity and technical limitations of the widely used BIOMED-2 primer sets and the MiSeq system (Illumina Inc., San Diego, CA) as an NGS application to assess the TCR repertoire. We evaluated replicate testing of individual libraries (th...

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Fractal Organization of the Human T Cell Repertoire in Health and after Stem Cell Transplantation

Cited by 54 publications

References 25 publications

On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments

On the organization of human T-cell receptor loci: log-periodic distribution of T-cell receptor gene segments

Abundant cytomegalovirus (CMV) reactive clonotypes in the CD8+ T cell receptor alpha repertoire following allogeneic transplantation

Methodologic Considerations in the Application of Next-Generation Sequencing of Human TRB Repertoires for Clinical Use

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