title: Regulatory T cell response correlates with the severity of human hantavirus infection.
abstract: OBJECTIVE
  Hantaviruses are an important group of emerging zoonotic pathogens, with significant mortality rates. Immunopathology is thought to be important in hantaviral disease, but the balance between protective and harmful responses is unknown. We studied Puumala hantavirus (PUUV) infection, which causes hemorrhagic fever with renal syndrome (HFRS) with a generally mild but highly variable clinical course.
  
  
  METHODS
  Clinical data and blood samples were collected from 24 patients with acute PUUV infection, and analyzed by flow cytometry and quantitative PCR.
  
  
  RESULTS
  The patients had a significantly increased frequency of CD4(+) and CD8(+) cells expressing the cell cycle marker Ki-67, but the magnitude of the effector T cell response did not correlate with disease severity. The frequency of FOXP3(+) regulatory T (Treg) cells expressing Ki-67 was also increased, and likewise did not correlate with disease outcome. In contrast, the level of FOXP3 expression, a surrogate of the suppressive phenotype, had a strong positive correlation with disease severity. This correlation was also found in samples taken 6-12 months after the HFRS.
  
  
  CONCLUSIONS
  The best predictor of a severe disease course in HFRS was the FOXP3(+) Treg cell response, suggesting that the role of Treg cells in acute human hantaviral infections may be deleterious.
authors.affiliation: Department of Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; Research Programs Unit, Immunobiology, Haartman Institute, University of Helsinki, Helsinki, Finland. Electronic address: tuisku.koivula@helsinki.fi.
authors.forename: Tuisku-Tuulia
authors.initials: TT
authors.lastname: Koivula
authors.affiliation: Department of Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; Research Programs Unit, Immunobiology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Anni
authors.initials: A
authors.lastname: Tuulasvaara
authors.affiliation: Department of Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; Research Programs Unit, Immunobiology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Iivo
authors.initials: I
authors.lastname: Hetemäki
authors.affiliation: Department of Medicine, University of Tampere School of Medicine, Tampere, Finland; Department of Internal Medicine, Tampere University Hospital, Tampere, Finland.
authors.forename: Satu Marjo
authors.initials: SM
authors.lastname: Mäkelä
authors.affiliation: Department of Medicine, University of Tampere School of Medicine, Tampere, Finland.
authors.forename: Jukka
authors.initials: J
authors.lastname: Mustonen
authors.affiliation: Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Tarja
authors.initials: T
authors.lastname: Sironen
authors.affiliation: Department of Virology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: Antti
authors.initials: A
authors.lastname: Vaheri
authors.affiliation: Department of Immunology, Haartman Institute, University of Helsinki, Helsinki, Finland; Research Programs Unit, Immunobiology, Haartman Institute, University of Helsinki, Helsinki, Finland.
authors.forename: T Petteri
authors.initials: TP
authors.lastname: Arstila
mesh_terms: D000328:Adult; D000368:Aged; D015704:CD4 Antigens / Q000032:analysis; D016827:CD8 Antigens / Q000032:analysis; D005260:Female; D005434:Flow Cytometry; D051858:Forkhead Transcription Factors / Q000032:analysis; D006480:Hemorrhagic Fever with Renal Syndrome / Q000276:immunology* / Q000473:pathology*; D006801:Humans; D016130:Immunophenotyping; D019394:Ki-67 Antigen / Q000032:analysis; D008297:Male; D008875:Middle Aged; D029262:Puumala virus / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D012720:Severity of Illness Index; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D055815:Young Adult
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D019394:Ki-67 Antigen
keywords: Hantavirus; Hemorrhagic fever with renal syndrome (HFRS); Regulatory T cell (Treg); T cell response