Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation
Simona Pagliuca, … , Betty K. Hamilton, Jaroslaw P. Maciejewski
Simona Pagliuca, … , Betty K. Hamilton, Jaroslaw P. Maciejewski
Published July 8, 2021
Citation Information: JCI Insight. ;6(13):e149080. https://doi.org/10.1172/jci.insight.149080.
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Research Article Hematology Immunology

Clinical and basic implications of dynamic T cell receptor clonotyping in hematopoietic cell transplantation

Abstract

TCR repertoire diversification constitutes a foundation for successful immune reconstitution after allogeneic hematopoietic cell transplantation (allo-HCT). Deep TCR Vβ sequencing of 135 serial specimens from a cohort of 35 allo-HCT recipients/donors was performed to dissect posttransplant TCR architecture and dynamics. Paired analysis of clonotypic repertoires showed a minimal overlap with donor expansions. Rarefied and hyperexpanded clonotypic patterns were hallmarks of T cell reconstitution and influenced clinical outcomes. Donor and pretransplant TCR diversity as well as divergence of class I human leukocyte antigen genotypes were major predictors of recipient TCR repertoire recovery. Complementary determining region 3–based specificity spectrum analysis indicated a predominant expansion of pathogen- and tumor-associated clonotypes in the late post–allo-HCT phase, while autoreactive clones were more expanded in the case of graft-versus-host disease occurrence. These findings shed light on post–allo-HCT adaptive immune reconstitution processes and possibly help in tracking alloreactive responses.

Authors

Simona Pagliuca, Carmelo Gurnari, Sanghee Hong, Ran Zhao, Sunisa Kongkiatkamon, Laila Terkawi, Misam Zawit, Yihong Guan, Hassan Awada, Ashwin Kishtagari, Cassandra M. Kerr, Thomas LaFramboise, Bhumika J. Patel, Babal K. Jha, Hetty E. Carraway, Valeria Visconte, Navneet S. Majhail, Betty K. Hamilton, Jaroslaw P. Maciejewski

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Figure 5

Structure of TCR repertoire at acute GVHD onset.

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Structure of TCR repertoire at acute GVHD onset. (A) Number of unique cl...
(A) Number of unique clonotypes at onset of acute GVHD (n = 5, red) and matched patients never developing a GVHD (n = 5). Violin plot. One dot per sample. Wilcoxon rank sum test (P = 0.814). (B) Number of unique pathologically expanded clonotypes in GVHD and non-GVHD groups. Violin plot. One dot per sample. Wilcoxon rank sum test (P = 0.690). (C) ISI distribution in GVHD and non-GVHD groups. Box plots depicting median and IQR. One dot per sample. Wilcoxon rank sum test (P = 0.792). (D) Size of pathologically expanded clonotypes in GVHD and non-GVHD groups. Violin plot: y axis expressed in log10 scale. One dot per clonotype. Wilcoxon rank sum test (P = 0.00096). (E) Proportion of nonexpanded, normally expanded, and pathologically expanded specificities. (F) Structural organization of the pathologically expanded portion of the repertoire. Bar plot representing each unique clonotype (each color) with its clonal size (area occupied by each color); y axis: proportion of occupancy of the pathologically expanded clonal space. The hyperexpanded group belong to all the clonotypes of size larger than 100. (G) Bubble chart illustrating the number (x axis) and mean size of expansion (bubble size) of clonotypes with known specificities in GVHD (red) and non-GVHD (light blue) groups (Supplemental Table 6A for rearrangement and annotation details). Of note, a selection of most represented disease-pathogen associated groups is captured. (H) Longitudinal analysis of 1 index case (CCF43) with clonotype analysis of pre-GVHD (day +30) and GVHD sample (day +90). Multicolor bars indicate proportion of occupancy of pathological clonal space for each unique clonotype (each color) and respective clonal size (bar area). Note: To capture all specificities in samples in the study analysis, in H the analysis was performed on the nondownsampled data set, with specificity frequency calculated as (# templates of each unique clonotype [clonal size]/total depth [total # templates]) × 100. Total depth: 24339 pre-GVHD, 70832 GVHD (Supplemental Table 6C).