title: Altered phenotype and functionality of varicella zoster virus-specific cellular immunity in individuals with active infection.
abstract: BACKGROUND
  Varicella zoster virus (VZV) establishes lifelong persistence and may reactivate in individuals with impaired immune function. To investigate immunologic correlates of protection and VZV reactivation, we characterized specific immunity in 207 nonsymptomatic immunocompetent and 132 immunocompromised individuals in comparison with patients with acute herpes zoster.
  
  
  METHODS
  VZV-specific CD4 T cells were quantified flow cytometrically after stimulation and characterized for expression of interferon-γ, interleukin 2, and tumor necrosis factor α and surface markers for differentiation (CD127) and anergy (cytotoxic T lymphocyte antigen 4 [CTLA-4] and programmed death [PD]-1). Immunoglobulin G and A levels were quantified using an enzyme-linked immunosorbent assay.
  
  
  RESULTS
  In healthy individuals, VZV-specific antibody and T-cell levels were age dependent, with the highest median VZV-specific CD4 T-cell frequencies of 0.108% (interquartile range, 0.121%) during adolescence. VZV-specific T-cell profiles were multifunctional with predominant expression of all 3 cytokines, CD127 positivity, and low expression of CTLA-4 and PD-1. Nonsymptomatic immunocompromised patients had similar VZV-specific immunologic properties except for lower T-cell frequencies (P<.001) and restricted cytokine expression. In contrast, significantly elevated antibody- and VZV-specific CD4 T-cell levels were found in patients with zoster. Their specific T cells showed a shift in cytokine expression toward interferon γ single positivity, an increase in CTLA-4 and PD-1, and a decrease in CD127 expression (all P<.001). This phenotype normalized after resolution of symptoms.
  
  
  CONCLUSIONS
  VZV-specific CD4-T cells in patients with zoster bear typical features of anergy. This phenotype is reversible and may serve as adjunct tool for monitoring VZV reactivations in high-risk patients.
authors.affiliation: Department of Transplant and Infection Immunology.
authors.forename: David
authors.initials: D
authors.lastname: Schub
authors.affiliation: Department of Dermatology.
authors.forename: Eva
authors.initials: E
authors.lastname: Janssen
authors.affiliation: Department of Internal Medicine IV.
authors.forename: Sarah
authors.initials: S
authors.lastname: Leyking
authors.affiliation: Department of Internal Medicine IV.
authors.forename: Urban
authors.initials: U
authors.lastname: Sester
authors.affiliation: Department of Internal Medicine I.
authors.forename: Gunter
authors.initials: G
authors.lastname: Assmann
authors.affiliation: Department of Pediatrics.
authors.forename: Pia
authors.initials: P
authors.lastname: Hennes
authors.affiliation: Institute of Virology, Saarland University, Homburg, Germany.
authors.forename: Sigrun
authors.initials: S
authors.lastname: Smola
authors.affiliation: Department of Dermatology.
authors.forename: Thomas
authors.initials: T
authors.lastname: Vogt
authors.affiliation: Department of Pediatrics.
authors.forename: Tilman
authors.initials: T
authors.lastname: Rohrer
authors.affiliation: Department of Transplant and Infection Immunology.
authors.forename: Martina
authors.initials: M
authors.lastname: Sester
authors.affiliation: Department of Transplant and Infection Immunology.
authors.forename: Tina
authors.initials: T
authors.lastname: Schmidt
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000914:Antibodies, Viral / Q000097:blood; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D016207:Cytokines / Q000032:analysis / Q000276:immunology; D005260:Female; D006562:Herpes Zoster / Q000453:epidemiology* / Q000276:immunology* / Q000821:virology; D014645:Herpesvirus 3, Human / Q000276:immunology*; D006801:Humans; D007111:Immunity, Cellular / Q000276:immunology*; D016867:Immunocompromised Host / Q000276:immunology; D007223:Infant; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D013601:T-Lymphocytes / Q000276:immunology; D055815:Young Adult
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines
keywords: T cells; VZV; cellular immunity; herpes zoster; shingles; varicella zoster virus