Abstract

BACKGROUNDImpaired 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.METHODSIn the present study, we used high-throughput T cell receptor Vß 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.RESULTSThese analyses indicated that a clinical response was coincident with significant changes in the T cell receptor Vß 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.CONCLUSIONThese 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 REGISTRATIONAustralian New Zealand Clinical Trial Registry, ACTRN12613000981729.FUNDINGThis study was supported by funding from the National Health and Medical Research Council, Australia (APP1132519 and APP1062074).

Authors	Smith, Corey; Corvino, Dillon; Beagley, Leone; Rehan, Sweera; Neller, Michelle A; Crooks, Pauline; Matthews, Katherine K; Solomon, Matthew; Le Texier, Laetitia; Campbell, Scott; Francis, Ross S; Chambers, Daniel; Khanna, Rajiv
Journal	JOURNAL OF CLINICAL INVESTIGATION
Pages	5020-5032
Volume	129
Date	1/11/2019
Grant ID	APP1132519
Funding Body	National Health and Medical Research Council
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1172/JCI128323