title: T cells from patients with Candida sepsis display a suppressive immunophenotype.
abstract: BACKGROUND
  Despite appropriate therapy, Candida bloodstream infections are associated with a mortality rate of approximately 40%. In animal models, impaired immunity due to T cell exhaustion has been implicated in fungal sepsis mortality. The purpose of this study was to determine potential mechanisms of fungal-induced immunosuppression via immunophenotyping of circulating T lymphocytes from patients with microbiologically documented Candida bloodstream infections.
  
  
  METHODS
  Patients with blood cultures positive for any Candida species were studied. Non-septic critically ill patients with no evidence of bacterial or fungal infection were controls. T cells were analyzed via flow cytometry for cellular activation and for expression of positive and negative co-stimulatory molecules. Both the percentages of cells expressing particular immunophenotypic markers as well as the geometric mean fluorescence intensity (GMFI), a measure of expression of the number of receptors or ligands per cell, were quantitated.
  
  
  RESULTS
  Twenty-seven patients with Candida bloodstream infections and 16 control patients were studied. Compared to control patients, CD8 T cells from patients with Candidemia had evidence of cellular activation as indicated by increased CD69 expression while CD4 T cells had decreased expression of the major positive co-stimulatory molecule CD28. CD4 and CD8 T cells from patients with Candidemia expressed markers typical of T cell exhaustion as indicated by either increased percentages of or increased MFI for programmed cell death 1 (PD-1) or its ligand (PD-L1).
  
  
  CONCLUSIONS
  Circulating immune effector cells from patients with Candidemia display an immunophenotype consistent with immunosuppression as evidenced by T cell exhaustion and concomitant downregulation of positive co-stimulatory molecules. These findings may help explain why patients with fungal sepsis have a high mortality despite appropriate antifungal therapy. Development of immunoadjuvants that reverse T cell exhaustion and boost host immunity may offer one way to improve outcome in this highly lethal disorder.
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Andrej
authors.initials: A
authors.lastname: Spec
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Yuichiro
authors.initials: Y
authors.lastname: Shindo
authors.affiliation: Department of Pathology and Immunology, Division of Laboratory and Genomic Medicine, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Carey-Ann D
authors.initials: CA
authors.lastname: Burnham
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Strother
authors.initials: S
authors.lastname: Wilson
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Enyo A
authors.initials: EA
authors.lastname: Ablordeppey
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Evan R
authors.initials: ER
authors.lastname: Beiter
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Katherine
authors.initials: K
authors.lastname: Chang
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA.
authors.forename: Anne M
authors.initials: AM
authors.lastname: Drewry
authors.affiliation: Department of Medicine, Division of Infectious Diseases, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA. hotch@wustl.edu.|Department of Anesthesiology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA. hotch@wustl.edu.|Department of Surgery, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, MO, 63110, USA. hotch@wustl.edu.
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
mesh_terms: D000328:Adult; D000368:Aged; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism; D002175:Candida / Q000276:immunology / Q000472:pathogenicity*; D058387:Candidemia / Q000097:blood* / Q000276:immunology*; D005260:Female; D006801:Humans; D007165:Immunosuppression Therapy; D008297:Male; D008875:Middle Aged; D010641:Phenotype; D011446:Prospective Studies