title: Reduced IL-7 responsiveness defined by signal transducer and activator of transcription 5 phosphorylation in T cells may be a marker for increased risk of developing cytomegalovirus disease in patients after hematopoietic stem cell transplantation.
abstract: Cytomegalovirus (CMV) reactivation may lead to CMV disease associated with high morbidity and mortality in patients after hematopoietic stem cell transplantation (HSCT); the identification of clinically relevant markers may aid in the identification of patients at increased risk for developing CMV-associated complications. We evaluated the phosphorylation of signal transducer and activator of transcription 5 (STAT5) in CD4(+) T cells, CD8(+) T cells, and TCRγδ T cells in response to stimulation with IL-7 or IL-2 after HSCT by analyzing blood samples taken monthly 1 to 6 months after HSCT. Patients were monitored weekly with a quantitative PCR from the time of engraftment for CMV viral load in whole blood until at least day 100 after HSCT. We identified a correlation between clinical outcome regarding CMV replication and the ability to respond to IL-7 and IL-2 defined by STAT5 phosphorylation (pSTAT5). Patients with recurrent or prolonged CMV replications had significantly lower pSTAT5 upon stimulation of T cells with either IL-7 or IL-2 at time points 1 through 3 than those without CMV replication (P < .05). This was also found after stimulation of CD8(+) T cells at time point 2 (P < .05). We conclude that reduced responses to IL-7, reflected by pSTAT5, may represent a clinically relevant functional biomarker for individuals at increased risk for CMV reactivation; our data may also aid in designing better strategies to improve anti-CMV immune responses without increasing the risk of developing graft-versus-host disease.
authors.affiliation: Department of Medicine Huddinge, Section of Hematology, Karolinska Institutet, Stockholm, Sweden; Department of Pediatrics, Karolinska University Hospital, Stockholm, Sweden. Electronic address: lena.bercoff@gmail.com.
authors.forename: Lena
authors.initials: L
authors.lastname: Pérez-Bercoff
authors.affiliation: Department of Immunobiology, Yale University, New Haven, Connecticut.
authors.forename: Nalini K
authors.initials: NK
authors.lastname: Vudattu
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory Vaccine Center, Emory University, Atlanta, Georgia.
authors.forename: Siddappa N
authors.initials: SN
authors.lastname: Byrareddy
authors.affiliation: Centrum för Allogen Stamcellstransplantation, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Jonas
authors.initials: J
authors.lastname: Mattsson
authors.affiliation: Centrum för Allogen Stamcellstransplantation, Karolinska University Hospital, Stockholm, Sweden; Division of Therapeutic Immunology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Maeurer
authors.affiliation: Department of Medicine Huddinge, Section of Hematology, Karolinska Institutet, Stockholm, Sweden; Division of Hematology, Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Per
authors.initials: P
authors.lastname: Ljungman
mesh_terms: D000328:Adult; D015415:Biomarkers / Q000378:metabolism; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000502:physiology*; D003586:Cytomegalovirus Infections / Q000276:immunology / Q000473:pathology / Q000821:virology*; D005260:Female; D006086:Graft vs Host Disease / Q000276:immunology / Q000473:pathology / Q000821:virology*; D019337:Hematologic Neoplasms / Q000276:immunology / Q000473:pathology / Q000821:virology*; D018380:Hematopoietic Stem Cell Transplantation; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology; D015851:Interleukin-7 / Q000494:pharmacology; D008297:Male; D010766:Phosphorylation; D011446:Prospective Studies; D050799:STAT5 Transcription Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D016176:T-Lymphocyte Subsets / Q000187:drug effects / Q000276:immunology / Q000821:virology; D014184:Transplantation, Homologous; D019562:Viral Load; D014775:Virus Activation; D014779:Virus Replication
chemical_list: D015415:Biomarkers; C508605:IL7 protein, human; D007376:Interleukin-2; D015851:Interleukin-7; D050799:STAT5 Transcription Factor
keywords: Cytomegalovirus; Graft-versus-host disease; HSCT; Interleukin-2; Interleukin-7; Signal transducer and activator of transcription 5 (STAT5)