Quantitative Assessment of T Cell Clonotypes in Human Acute Graft-versus-Host Disease Tissues

Koyama, Daisuke; Murata, Makoto; Hanajiri, Ryo; Akashi, Tomohiro; Okuno, Shingo; Kamoshita, Sonoko; Julamanee, Jakrawadee; Takagi, Erina; Miyao, Kotaro; Sakemura, Reona; Goto, Tatsunori; Terakura, Seitaro; Nishida, Tetsuya; Kiyoi, Hitoshi

doi:10.1016/j.bbmt.2018.10.012

Cited by 20 publications

(11 citation statements)

References 20 publications

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“…Therefore, monitoring the longitudinal expansion of tissue-infiltrating clones in blood could be developed as a novel biomarker of GVHD disease activity. However, it is also reported that frequent clonotypes differ among tissues in the same patient with GVHD ( 14 ). Thus, the similarity of T-cell clones from tissue to tissue needs to be further studied in GVHD patients that might be affected by anatomy location of biopsy, stage after HCT, severity of GVHD, and treatment response.…”

Section: Discussionmentioning

confidence: 99%

“…They found that TCR reconstitution is highly stochastic and likely does not depend on the evaluation of the most expanded TCR clones in any individual recipient but instead depends on a complex polyclonal architecture. Similarly, the tissue-infiltrating TCRβ repertoires are highly patient specific after HCT ( 12 , 14 ). Interestingly, although the dominant clones were unique to each patient, GVHD patients shared a small number of clones that were exclusively found in steroid-refractory case ( 16 ).…”

Section: Discussionmentioning

confidence: 99%

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Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Wang

et al. 2021

Front. Immunol.

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The diversity and composition of T-cell receptor (TCR) repertoire, which is the result of V, (D), and J gene recombination in TCR gene locus, has been found to be implicated in T-cell responses in autoimmunity, cancer, and organ transplantation. The correlation of T-cell repertoire with the pathogenesis of graft-versus-host disease (GVHD) after allogeneic hematopoietic cell transplantation remains largely undefined. Here, by utilizing high-throughput sequencing of the genes encoding TCRβ-chain, we comprehensively analyzed the profile of T-cell repertoire in recipient lymphoid and GVHD target organs after bone marrow transplantation (BMT) in mice. In lymphoid organs, TCR diversity was narrowed, accompanied with reduced numbers of unique clones while increased accumulation of dominant clones in allogeneic T cells compared to syngeneic T cells. In an individual allogeneic recipient, donor-derived TCR clones were highly overlapped among tissue sites, and the degree of overlapping was increasing from day 7 to 14 after allogeneic BMT. The top clones in peripheral blood, gut, liver, and lungs were highly mutually shared in an allogenic recipient, indicating that blood has the potential to predict dominant clones in these GVHD target organs. T cells in GVHD target organs from allogeneic recipients had fewer overlapped clones with pre-transplant donor T cells compared to those from syngeneic recipients. Importantly, the top 10 clones in allogeneic recipients were not detectable in pre-transplant donor T cells, indicating clonal expansion of rare rearrangements. Interestingly, even starting from the same pool of donor repertoires, T cells had very few overlapped clones between each allogeneic recipient who developed completely different dominant clones. We were only able to trace a single clone shared by three replicate allogeneic recipients within the top 500 clones. Although dominant clones were different among allogeneic recipients, V26 genes were consistently used more frequently by TCR clones in allogeneic than syngeneic recipients. This is the first study to extensively examine the feature of T-cell repertoire in multiple lymphoid and parenchyma organs, which establishes the association between T-cell activation and GVHD pathogenesis at the level of TCR clones. Immune repertoire sequencing-based methods may represent a novel personalized strategy to guide diagnosis and therapy in GVHD.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Wang

et al. 2021

Front. Immunol.

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“…It is possible that although the exact identity of alloreactive clones causing GVHD may be different between individuals, their behavior may follow reproducible and measurable patterns. 4,[13][14][15] Murine experimental systems of HCT and GVHD offer the opportunity to understand and develop tools to measure TCR reconstitution in a controlled setting. 16 Many studies have specifically associated the presence of a restricted TCR VDJ gene usage or identified dominant T cells with GVHD.…”

Section: Introductionmentioning

confidence: 99%

Recipient-specific T-cell repertoire reconstitution in the gut following murine hematopoietic cell transplant

et al. 2020

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Graft-versus-host disease (GVHD) is a complication of hematopoietic cell transplantation (HCT) caused by alloreactive T cells. Murine models of HCT are used to understand GVHD and T-cell reconstitution in GVHD target organs, most notably the gastrointestinal (GI) tract where the disease contributes most to patient mortality. T-cell receptor (TCR) repertoire sequencing was used to measure T-cell reconstitution from the same donor graft (C57BL/6 H-2b) in the GI tract of different recipients across a spectrum of matching, from syngeneic (C57BL/6), to minor histocompatibility (MHC) antigen mismatch BALB.B (H-2b), to major MHC mismatched B10.BR (H-2k) and BALB/c (H-2d). Although the donor T-cell pools had highly similar TCR, the TCR repertoire after HCT was very specific to recipients in each experiment independent of geography. A single invariant natural killer T clone was identifiable in every recipient group and was enriched in syngeneic recipients according to clonal count and confirmatory flow cytometry. Using a novel cluster analysis of the TCR repertoire, we could classify recipient groups based only on their CDR3 size distribution or TCR repertoire relatedness. Using a method for evaluating the contribution of common TCR motifs to relatedness, we found that reproducible sets of clones were associated with specific recipient groups within each experiment and that relatedness did not necessarily depend on the most common clones in allogeneic recipients. This finding suggests that TCR reconstitution is highly stochastic and likely does not depend on the evaluation of the most expanded TCR clones in any individual recipient but instead depends on a complex polyclonal architecture.

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“…Along this line, Koyama et al. ( 39 ) reported that different T-cell clonotypes were detected in patients undergoing GVHD in the skin, colon, or blood of the very same patient, suggesting that HLA molecules present distinct peptides in various organs. In contrast, Michalek et al.…”

Section: Discussionmentioning

confidence: 97%

“…A refined peptidome analysis would be required to investigate this hypothesis further. Along this line, Koyama et al (39) reported that different T-cell clonotypes were detected in patients undergoing GVHD in the skin, colon, or blood of the very same patient, suggesting that HLA molecules present distinct peptides in various organs. In contrast, Michalek et al (40) reported the expansion of a unique specific CD4 + T-cell clone in the blood of an HSCT patient undergoing GVHD.…”

Section: Discussionmentioning

confidence: 98%

CD8+ T-Cell Repertoire in Human Leukocyte Antigen Class I-Mismatched Alloreactive Immune Response

et al. 2021

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In transplantation, direct allorecognition is a complex interplay between T-cell receptors (TCR) and HLA molecules and their bound peptides expressed on antigen-presenting cells. In analogy to HLA mismatched hematopoietic stem cell transplantation (HSCT), the TCR CDR3β repertoires of alloreactive cytotoxic CD8+ responder T cells, defined by the cell surface expression of CD137 and triggered in vitro by HLA mismatched stimulating cells, were analyzed in different HLA class I mismatched combinations. The same HLA mismatched stimulatory cells induced very different repertoires in distinct but HLA identical responders. Likewise, stimulator cells derived from HLA identical donors activated CD8+ cells expressing very different repertoires in the same mismatched responder. To mimic in vivo inflammation, expression of HLA class l antigens was upregulated in vitro on stimulating cells by the inflammatory cytokines TNFα and IFNβ. The repertoires differed whether the same responder cells were stimulated with cells treated or not with both cytokines. In conclusion, the selection and expansion of alloreactive cytotoxic T-cell clonotypes expressing a very diverse repertoire is observed repeatedly despite controlling for HLA disparities and is significantly influenced by the inflammatory status. This makes prediction of alloreactive T-cell repertoires a major challenge in HLA mismatched HSCT.

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Quantitative Assessment of T Cell Clonotypes in Human Acute Graft-versus-Host Disease Tissues

Cited by 20 publications

References 20 publications

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice

Recipient-specific T-cell repertoire reconstitution in the gut following murine hematopoietic cell transplant

CD8+ T-Cell Repertoire in Human Leukocyte Antigen Class I-Mismatched Alloreactive Immune Response

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