B cell-intrinsic signaling through IL-21 receptor and STAT3 is required for establishing long-lived antibody responses in humans.
Engagement of cytokine receptors by specific ligands activate Janus kinase-signal transducer and activator of transcription (STAT) signaling pathways. The exact roles of STATs in human lymphocyte behavior remain incompletely defined. Interleukin (IL)-21 activates STAT1 and STAT3 and has emerged as a potent regulator of B cell differentiation. We have studied patients with inactivating mutations in STAT1 or STAT3 to dissect their contribution to B cell function in vivo and in response to IL-21 in vitro. STAT3 mutations dramatically reduced the number of functional, antigen (Ag)-specific memory B cells and abolished the ability of IL-21 to induce naive B cells to differentiate into plasma cells (PCs). This resulted from impaired activation of the molecular machinery required for PC generation. In contrast, STAT1 deficiency had no effect on memory B cell formation in vivo or IL-21-induced immunoglobulin secretion in vitro. Thus, STAT3 plays a critical role in generating effector B cells from naive precursors in humans. STAT3-activating cytokines such as IL-21 thus underpin Ag-specific humoral immune responses and provide a mechanism for the functional antibody deficit in STAT3-deficient patients.
Avery
Danielle T
DT
Immunology Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
Deenick
Elissa K
EK
Ma
Cindy S
CS
Suryani
Santi
S
Simpson
Nicholas
N
Chew
Gary Y
GY
Chan
Tyani D
TD
Palendira
Umamainthan
U
Bustamante
Jacinta
J
Boisson-Dupuis
Stéphanie
S
Choo
Sharon
S
Bleasel
Karl E
KE
Peake
Jane
J
King
Cecile
C
French
Martyn A
MA
Engelhard
Dan
D
Al-Hajjar
Sami
S
Al-Muhsen
Saleh
S
Magdorf
Klaus
K
Roesler
Joachim
J
Arkwright
Peter D
PD
Hissaria
Pravin
P
Riminton
D Sean
DS
Wong
Melanie
M
Brink
Robert
R
Fulcher
David A
DA
Casanova
Jean-Laurent
JL
Cook
Matthew C
MC
Tangye
Stuart G
SG
D000917:Antibody Formation / Q000502:physiology; D000941:Antigens / Q000235:genetics / Q000276:immunology; D002454:Cell Differentiation / Q000502:physiology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000276:immunology; D007156:Immunologic Memory / Q000502:physiology*; D007378:Interleukins / Q000235:genetics / Q000276:immunology*; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology*; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000276:immunology; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000276:immunology*; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D000098546:Interleukin-21
D000941:Antigens; D007136:Immunoglobulins; D007378:Interleukins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000098546:Interleukin-21