Persistence of EBV antigen-specific CD8 T cell clonotypes during homeostatic immune reconstitution in cancer patients

• Published in: PloS one Vol. 8; no. 10; p. e78686
• Main Authors: Iancu, Emanuela M, Gannon, Philippe O, Laurent, Julien, Gupta, Bhawna, Romero, Pedro, Michielin, Olivier, Romano, Emanuela, Speiser, Daniel E, Rufer, Nathalie
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 25.10.2013; Public Library of Science (PLoS)
• Subjects: Activation; Adult; Aged; Amino Acid Sequence; Antigens; Antigens, Viral - immunology; Cancer; CCR5 protein; CD27 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation; Chemotherapy; Clone Cells - immunology; Cytomegalovirus; Epstein-Barr virus; Gene expression; Herpesvirus 4, Human - immunology; HIV; Homeostasis; Homing; Human immunodeficiency virus; Humans; Immune reconstitution; Immunology; Infections; Interleukin 7 receptors; L-selectin; Lymphocytes; Lymphocytes T; Medical research; Melanoma; Melanoma - immunology; Melanoma - virology; Memory; Middle Aged; Oncology; Patients; Priming; Receptors, Antigen, T-Cell - chemistry; Receptors, Antigen, T-Cell - metabolism; T cell receptors; T-cell receptor; Time Factors; Viral infections; Viruses; Switzerland
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0078686

Persistent viruses are kept in check by specific lymphocytes. The clonal T cell receptor (TCR) repertoire against Epstein-Barr virus (EBV), once established following primary infection, exhibits a robust stability over time. However, the determinants contributing to this long-term persistence are still poorly characterized. Taking advantage of an in vivo clinical setting where lymphocyte homeostasis was transiently perturbed, we studied EBV antigen-specific CD8 T cells before and after non-myeloablative lympho-depleting chemotherapy of melanoma patients. Despite more advanced T cell differentiation, patients T cells showed clonal composition comparable to healthy individuals, sharing a preference for TRBV20 and TRBV29 gene segment usage and several co-dominant public TCR clonotypes. Moreover, our data revealed the presence of relatively few dominant EBV antigen-specific T cell clonotypes, which mostly persisted following transient lympho-depletion (TLD) and lymphocyte recovery, likely related to absence of EBV reactivation and de novo T cell priming in these patients. Interestingly, persisting clonotypes frequently co-expressed memory/homing-associated genes (CD27, IL7R, EOMES, CD62L/SELL and CCR5) supporting the notion that they are particularly important for long-lasting CD8 T cell responses. Nevertheless, the clonal composition of EBV-specific CD8 T cells was preserved over time with the presence of the same dominant clonotypes after non-myeloablative chemotherapy. The observed clonotype persistence demonstrates high robustness of CD8 T cell homeostasis and reconstitution.