Tracking genetically engineered lymphocytes long-term reveals the dynamics of t cell immunological memory

Giacomo Oliveira, Eliana Ruggiero, Maria Teresa Lupo Stanghellini, Nicoletta Cieri, Mattia D'Agostino, Raffaele Fronza, Christina Lulay, Francesca Dionisio, Sara Mastaglio, Raffaella Greco, Jacopo Peccatori, Alessandro Aiuti, Alessandro Ambrosi, Luca Biasco, Attilio Bondanza, Antonio Lambiase, Catia Traversari, Luca Vago, Christof Von Kalle, Manfred SchmidtClaudio Bordignon, Fabio Ciceri, Chiara Bonini

Research output: Contribution to journalArticle

Abstract

Long-lasting immune protection from pathogens and cancer requires the generation of memory T cells able to survive long-term. To unravel the immunological requirements for long-term persistence of human memory T cells, we characterized and traced, over several years, T lymphocytes genetically modified to express the thymidine kinase (TK) suicide gene that were infused in 10 patients after haploidentical hematopoietic stem cell transplantation (HSCT). At 2 to 14 years after infusion and in the presence of a broad and resting immune system, we could still detect effectors/effector memory (TEM/EFF), central memory (TCM), and stem memory (TSCM) TK+ cells, circulating at low but stable levels in all patients. Longitudinal analysis of cytomegalovirus (CMV)- and Flu-specific TK+ cells indicated that antigen recognition was dominant in driving in vivo expansion and persistence at detectable levels. The amount of infused TSCM cells positively correlated with early expansion and with the absolute counts of long-term persisting gene-marked cells. By combining T cell sorting with sequencing of integration (IS), TCRa and TCRb clonal markers, we showed that T cells retrieved long-term were enriched in clones originally shared in different memory T cell subsets, whereas dominant long-term clonotypes appeared to preferentially originate from infused TSCM and TCM clones. Together, these results indicate that long-term persistence of gene-modified memory T cells after haploidentical HSCT is influenced by antigen exposure and by the original phenotype of infused cells. Cancer adoptive immunotherapy might thus benefit from cellular products enriched in lymphocytes with an early-differentiated phenotype.

Original languageEnglish
Article number8265
JournalScience Translational Medicine
Volume7
Issue number317
DOIs
Publication statusPublished - Dec 9 2015

ASJC Scopus subject areas

  • Medicine(all)

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