Faculty Collaboration Database

Donor T-Cell Repertoire Profiling in Recipient Lymphoid and Parenchyma Organs Reveals GVHD Pathogenesis at Clonal Levels After Bone Marrow Transplantation in Mice. Front Immunol 2021;12:778996

Date

12/25/2021

Pubmed ID

34950143

Pubmed Central ID

PMC8688739

DOI

10.3389/fimmu.2021.778996

Scopus ID

2-s2.0-85121630632 (requires institutional sign-in at Scopus site)   3 Citations

Abstract

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.

Author List

Wu Y, Fu J, Wang H, Yu XZ

Authors

Yongxia Wu PhD Assistant Professor in the Microbiology and Immunology department at Medical College of Wisconsin
Xue-Zhong Yu MD Professor in the Microbiology and Immunology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Bone Marrow Transplantation
Clonal Selection, Antigen-Mediated
Disease Models, Animal
Gene Expression Profiling
Genes, T-Cell Receptor beta
Graft vs Host Disease
High-Throughput Nucleotide Sequencing
Homeodomain Proteins
Lymphocyte Activation
Lymphoid Tissue
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Knockout
Phenotype
T-Lymphocytes
Time Factors
Transcriptome
Transplantation, Homologous
Transplantation, Isogeneic
Whole-Body Irradiation