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 1

Structural organization of TCR repertoire in controls and patients before hematopoietic cell transplantation.

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Structural organization of TCR repertoire in controls and patients befor...
(A) Clonotype size of healthy controls (HC, n = 131; red dots) and donors (n = 14; purple dots). Only expanded clonotypes are plotted (size greater than 1 template); y axis: size of each clonotype expressed in logarithmic scale (base 10); x axis: samples belonging to each group. Each dot represents a clonotype (rearrangement details in Supplemental Table 2A). (B) Mean size of all expanded clonotypes (size greater than 1 template), for HC (red dots) and donors (purple dots). Dot plot representing the mean size of expansion in 1 sample (donors: n = 14, HC: n = 131). The gray area configures the range of pathological expansion. Mean size of expansion: 4.72 (95% CI 4.31–5.12), gray dotted line: 5.12 (metrics details in Supplemental Table 2B). (C) ISI distribution in HC (n = 131) and donors (n = 14). Violin plots. Mean HC: 2488.94 (95% CI 2205–2772); Mean donors: 2826 (95% CI 1726–3926). Each dot represents the ISI in 1 sample (donors: n = 14, HC: n = 131). Wilcoxon rank sum test (P = 0.604). (D) Number of unique clonotypes in HC and donors (n = 145). Violin plots. Mean: 4886 (95% CI: 4812–4959). One dot per sample. (E) Number of unique expanded clonotypes in HC and donors (n = 145). Violin plot. Mean: 136 (95% CI: 124–148). One dot per sample. (F) Mean size of pathological expansion in HC and donors (n = 145). Violin plot. Mean: 15 (95% CI: 13–17). One dot per sample. (G) Proportion of repertoire overlapping between 2 healthy donors (Supplemental Table 3A). (H) Left: Pie charts representing the distribution of the known specificities of the clonotypes overlapping in donors in the three portions of the repertoire (whole, expanded and pathologically expanded). Right: Bubble chart depicting the number (y axis) and the mean size of expansion (bubble size) of overlapping clonotypes with known specificities (Supplemental Table 3B for rearrangement and annotation details). All of the analyses described here have been performed on the downsampled data set.