title: Early exposure to interleukin-21 limits rapidly generated anti-Epstein-Barr virus T-cell line differentiation.
abstract: OBJECTIVE
  The adoptive transfer of ex vivo-expanded Epstein-Barr virus (EBV)-specific T-cell lines is an attractive strategy to treat EBV-related neoplasms. Current evidence suggests that for adoptive immunotherapy in general, clinical responses are superior if the transferred cells have not reached a late or terminal effector differentiation phenotype before infusion. The cytokine interleukin (IL)-21 has shown great promise at limiting late T-cell differentiation in vitro, but this remains to be demonstrated in anti-viral T-cell lines.
  
  
  METHODS
  We adapted a clinically validated protocol to rapidly generate EBV-specific T-cell lines in 12 to 14 days and tested whether the addition of IL-21 at the initiation of the culture would affect T-cell expansion and differentiation.
  
  
  RESULTS
  We generated clinical-scale EBV-restricted T-cell line expansion with balanced T-cell subset ratios. The addition of IL-21 at the beginning of the culture decreased both T-cell expansion and effector memory T-cell accumulation, with a relative increase in less-differentiated T cells. Within CD4 T-cell subsets, exogenous IL-21 was notably associated with the cell surface expression of CD27 and high KLF2 transcript levels, further arguing for a role of IL-21 in the control of late T-cell differentiation.
  
  
  CONCLUSIONS
  Our results show that IL-21 has profound effects on T-cell differentiation in a rapid T-cell line generation protocol and as such should be further explored as a novel approach to program anti-viral T cells with features associated with early differentiation and optimal therapeutic efficacy.
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada.
authors: Julie
authors: J
authors: Orio
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada.
authors: Cédric
authors: C
authors: Carli
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada.
authors: Valérie
authors: V
authors: Janelle
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada.
authors: Martin
authors: M
authors: Giroux
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada.
authors: Julie
authors: J
authors: Taillefer
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada.
authors: Mathieu
authors: M
authors: Goupil
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada.
authors: Manon
authors: M
authors: Richaud
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada; Hematology-Oncology Division, Hôpital Maisonneuve-Rosemont, Quebec, Canada; Department of Medicine, University of Montréal, Quebec, Canada.
authors: Denis-Claude
authors: DC
authors: Roy
authors: Hôpital Maisonneuve-Rosemont Research Centre, Quebec, Canada; Hematology-Oncology Division, Hôpital Maisonneuve-Rosemont, Quebec, Canada; Department of Medicine, University of Montréal, Quebec, Canada. Electronic address: js.delisle@umontreal.ca.
authors: Jean-Sébastien
authors: JS
authors: Delisle
mesh_terms: D019264:Adoptive Transfer; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D002460:Cell Line; D020031:Epstein-Barr Virus Infections / Q000628:therapy*; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007378:Interleukins / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D009369:Neoplasms / Q000628:therapy* / Q000821:virology; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000637:transplantation; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D000098546:Interleukin-21
keywords: CD27; Epstein-Barr virus; IL-21; T cell; T-cell memory; adoptive immunotherapy