T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response
Corey Smith, … , Daniel Chambers, Rajiv Khanna
Corey Smith, … , Daniel Chambers, Rajiv Khanna
Published November 1, 2019; First published August 15, 2019
Citation Information: J Clin Invest. 2019;129(11):5020-5032. https://doi.org/10.1172/JCI128323.
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Clinical Medicine Immunology Transplantation

T cell repertoire remodeling following post-transplant T cell therapy coincides with clinical response

Abstract

BACKGROUND Impaired T cell immunity in transplant recipients is associated with infection-related morbidity and mortality. We recently reported the successful use of adoptive T cell therapy (ACT) against drug-resistant/recurrent cytomegalovirus in solid-organ transplant recipients.METHODS In the present study, we used high-throughput T cell receptor Vβ sequencing and T cell functional profiling to delineate the impact of ACT on T cell repertoire remodeling in the context of pretherapy immunity and ACT products.RESULTS These analyses indicated that a clinical response was coincident with significant changes in the T cell receptor Vβ landscape after therapy. This restructuring was associated with the emergence of effector memory T cells in responding patients, while nonresponders displayed dramatic pretherapy T cell expansions with minimal change following ACT. Furthermore, immune reconstitution included both adoptively transferred clonotypes and endogenous clonotypes not detected in the ACT products.CONCLUSION These observations demonstrate that immune control following ACT requires significant repertoire remodeling, which may be impaired in nonresponders because of the preexisting immune environment. Immunological interventions that can modulate this environment may improve clinical outcomes.TRIAL REGISTRATION Australian New Zealand Clinical Trial Registry, ACTRN12613000981729.FUNDING This study was supported by funding from the National Health and Medical Research Council, Australia (APP1132519 and APP1062074).

Authors

Corey Smith, Dillon Corvino, Leone Beagley, Sweera Rehan, Michelle A. Neller, Pauline Crooks, Katherine K. Matthews, Matthew Solomon, Laetitia Le Texier, Scott Campbell, Ross S. Francis, Daniel Chambers, Rajiv Khanna

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Figure 8

CMV-specific T cell frequency and phenotype following ACT.

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CMV-specific T cell frequency and phenotype following ACT. The frequency...
The frequency and phenotype of CMV-specific T cells pretherapy and at long-term follow-up were assessed using HLA-matched MHC multimer analysis and the expression of CD27, CD28, CD45RA, CD57, CCR7, and CD95. (A) Data represent the frequency of HLA-matched MHC multimer–specific T cells (left axis) overlaid with the frequency of CMV-specific IFN-γ–producing CD8+ T cells (right axis). (B) Concatenated files were prepared from patient samples at each time point and tSNE analysis used to establish phenotypic populations in CD8+ T cells, including naive, central memory (CM1 and CM2), and effector memory (EM1, EM2, and EM3). The gating strategy for each population and fluorescence intensity for each surface marker are shown in Supplemental Figure 3. Left panels represent the CD8+ T cell populations in 4 responding patients. Data in the middle and right panels are overlaid with the corresponding MHC multimer–specific population.