Abstract
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.
Highlights
Primary Epstein-Barr virus (EBV) infection is associated with massive viral replication
Severe immunosuppression following transplantation or human immunodeficiency virus (HIV) infection can result in deficient EBV-specific immunity, which may lead to EBV-associated pathology such as lymphoproliferative disease
Transient lympho-depletion (TLD) induced by nonmyeloablative chemotherapy has become of high interest in the field of cancer immunotherapy, as it strongly favors in vivo survival and expansion of adoptively transferred cells [31,36,37,38]
Summary
Primary Epstein-Barr virus (EBV) infection is associated with massive viral replication. In spite of the generation of a robust T cell specific immune response, EBV establishes a latent infection in B cells [1]. Healthy EBV-infected individuals remain asymptomatic throughout their life due to viral containment by antigen-specific memory CD8 T lymphocytes [1,2,3]. As increasing attention is devoted to optimizing therapeutic vaccination strategies against cancer, the immune control of chronic EBV infection represents an interesting model system to study the mechanisms involved in the generation and maintenance of life-long protective immune responses. Memory-like T cells display long-term survival and self-renewal abilities, high proliferative potential, and the capacity to rapidly and efficiently produce effector cells in response to antigen re-encounter [7,8,9]. Effector T cells have the capacity to migrate to the site of inflammation, to kill antigen-bearing target cells and secrete various cytokines (e.g. IFNγ, TNFα) [10]
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