title: Signal transducer and activator of transcription 3 (STAT3) mutations underlying autosomal dominant hyper-IgE syndrome impair human CD8(+) T-cell memory formation and function.
abstract: BACKGROUND
  The capacity of CD8(+) T cells to control infections and mediate antitumor immunity requires the development and survival of effector and memory cells. IL-21 has emerged as a potent inducer of CD8(+) T-cell effector function and memory development in mouse models of infectious disease. However, the role of IL-21 and associated signaling pathways in protective CD8(+) T-cell immunity in human subjects is unknown.
  
  
  OBJECTIVE
  We sought to determine which signaling pathways mediate the effects of IL-21 on human CD8(+) T cells and whether defects in these pathways contribute to disease pathogenesis in patients with primary immunodeficiencies caused by mutations in components of the IL-21 signaling cascade.
  
  
  METHODS
  Human primary immunodeficiencies resulting from monogenic mutations provide a unique opportunity to assess the requirement for particular molecules in regulating human lymphocyte function. Lymphocytes from patients with loss-of-function mutations in signal transducer and activator of transcription 1 (STAT1), STAT3, or IL-21 receptor (IL21R) were used to assess the respective roles of these genes in human CD8(+) T-cell differentiation in vivo and in vitro.
  
  
  RESULTS
  Mutations in STAT3 and IL21R, but not STAT1, led to a decrease in multiple memory CD8(+) T-cell subsets in vivo, indicating that STAT3 signaling, possibly downstream of IL-21R, regulates the memory cell pool. Furthermore, STAT3 was important for inducing the lytic machinery in IL-21-stimulated naive CD8(+) T cells. However, this defect was overcome by T-cell receptor engagement.
  
  
  CONCLUSIONS
  The IL-21R/STAT3 pathway is required for many aspects of human CD8(+) T-cell behavior but in some cases can be compensated by other signals. This helps explain the relatively mild susceptibility to viral disease observed in STAT3- and IL-21R-deficient subjects.
authors.affiliation: Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, Australia.
authors.forename: Megan L
authors.initials: ML
authors.lastname: Ives
authors.forename: Cindy S
authors.initials: CS
authors.lastname: Ma
authors.forename: Umaimainthan
authors.initials: U
authors.lastname: Palendira
authors.forename: Anna
authors.initials: A
authors.lastname: Chan
authors.forename: Jacinta
authors.initials: J
authors.lastname: Bustamante
authors.forename: Stephanie
authors.initials: S
authors.lastname: Boisson-Dupuis
authors.forename: Peter D
authors.initials: PD
authors.lastname: Arkwright
authors.forename: Dan
authors.initials: D
authors.lastname: Engelhard
authors.forename: Diana
authors.initials: D
authors.lastname: Averbuch
authors.forename: Klaus
authors.initials: K
authors.lastname: Magdorf
authors.forename: Joachim
authors.initials: J
authors.lastname: Roesler
authors.forename: Jane
authors.initials: J
authors.lastname: Peake
authors.forename: Melanie
authors.initials: M
authors.lastname: Wong
authors.forename: Stephen
authors.initials: S
authors.lastname: Adelstein
authors.forename: Sharon
authors.initials: S
authors.lastname: Choo
authors.forename: Joanne M
authors.initials: JM
authors.lastname: Smart
authors.forename: Martyn A
authors.initials: MA
authors.lastname: French
authors.forename: David A
authors.initials: DA
authors.lastname: Fulcher
authors.forename: Matthew C
authors.initials: MC
authors.lastname: Cook
authors.forename: Capucine
authors.initials: C
authors.lastname: Picard
authors.forename: Anne
authors.initials: A
authors.lastname: Durandy
authors.forename: Miyuki
authors.initials: M
authors.lastname: Tsumura
authors.forename: Masao
authors.initials: M
authors.lastname: Kobayashi
authors.forename: Gulbu
authors.initials: G
authors.lastname: Uzel
authors.forename: Jean-Laurent
authors.initials: JL
authors.lastname: Casanova
authors.forename: Stuart G
authors.initials: SG
authors.lastname: Tangye
authors.forename: Elissa K
authors.initials: EK
authors.lastname: Deenick
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000166:cytology* / Q000276:immunology / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D006801:Humans; D007156:Immunologic Memory; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D007589:Job Syndrome / Q000235:genetics* / Q000276:immunology / Q000473:pathology; D009154:Mutation; D053655:Receptors, Interleukin-21 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D000098546:Interleukin-21
chemical_list: D007378:Interleukins; D053655:Receptors, Interleukin-21; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21
keywords: AD-HIES; Autosomal dominant hyper-IgE syndrome; B-cell lymphoma; BCL; CTV; CellTrace Violet; Central memory T; EOMES; Effector memory T; Effector memory T cells expressing CD45RA; Eomesodermin; IL-21; IL-21 receptor; IL-21R; LCMV; Lymphocytic choriomeningitis virus; PB; PID; Peripheral blood; Primary immunodeficiency; STAT; STAT1; STAT3; Signal transducer and activator of transcription; T(CM); T(EM); T(EMRA); T-cell receptor; TCR; differentiation; human CD8(+) T cells; memory