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 4

Donor-recipient overlap analysis.

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Donor-recipient overlap analysis. (A) Proportion of de novo and overlapp...
(A) Proportion of de novo and overlapping specificities at day +30, +100, and +180. Rearrangement details and number of donor-recipient shared clonotypes are reported in Supplemental Table 5, A and B. (B) Proportion of donor-recipient shared specificities after subtraction of public interindividual overlap (0.9% of repertoire). (C) Origin of shared clonotypes according to clonal expansion in recipients and donors (Supplemental Table 5C). The first set of pie charts (blue for nonexpanded, yellow for normal expanded, red for pathologically expanded) refers to the status of clonal expansion in recipients at the 3 time points. The second and third set of pie charts refer instead to the proportion of donor repertoires at the origin of nonexpanded (blue) and pathologically expanded (red) clonotypic fractions in recipients. (D) Distribution of the known specificities of donor-recipient overlapping clonotypes in posttransplant groups. (E) Bubble chart depicting the number (x axis) and the mean size of expansion (bubble size) of donor-recipient overlapping clonotypes with known specificities (Supplemental Table 5A for rearrangement and annotation details). Of note only a selection of most represented disease/pathogen associated groups is captured in the figure for visualization purposes. All of the analyses described here have been performed on the downsampled data set.