Naive and memory human B cells have distinct requirements for STAT3 activation to differentiate into antibody-secreting plasma cells.
Long-lived antibody memory is mediated by the combined effects of long-lived plasma cells (PCs) and memory B cells generated in response to T cell-dependent antigens (Ags). IL-10 and IL-21 can activate multiple signaling pathways, including STAT1, STAT3, and STAT5; ERK; PI3K/Akt, and potently promote human B cell differentiation. We previously showed that loss-of-function mutations in STAT3, but not STAT1, abrogate IL-10- and IL-21-mediated differentiation of human naive B cells into plasmablasts. We report here that, in contrast to naive B cells, STAT3-deficient memory B cells responded to these STAT3-activating cytokines, differentiating into plasmablasts and secreting high levels of IgM, IgG, and IgA, as well as Ag-specific IgG. This was associated with the induction of the molecular machinery necessary for PC formation. Mutations in IL21R, however, abolished IL-21-induced responses of both naive and memory human B cells and compromised memory B cell formation in vivo. These findings reveal a key role for IL-21R/STAT3 signaling in regulating human B cell function. Furthermore, our results indicate that the threshold of STAT3 activation required for differentiation is lower in memory compared with naive B cells, thereby identifying an intrinsic difference in the mechanism underlying differentiation of naive versus memory B cells.
Immunology and Immunodeficiency Group, Immunology Research Program, Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
Elissa K
EK
Deenick
Danielle T
DT
Avery
Anna
A
Chan
Lucinda J
LJ
Berglund
Megan L
ML
Ives
Leen
L
Moens
Jennifer L
JL
Stoddard
Jacinta
J
Bustamante
Stephanie
S
Boisson-Dupuis
Miyuki
M
Tsumura
Masao
M
Kobayashi
Peter D
PD
Arkwright
Diana
D
Averbuch
Dan
D
Engelhard
Joachim
J
Roesler
Jane
J
Peake
Melanie
M
Wong
Stephen
S
Adelstein
Sharon
S
Choo
Joanne M
JM
Smart
Martyn A
MA
French
David A
DA
Fulcher
Matthew C
MC
Cook
Capucine
C
Picard
Anne
A
Durandy
Christoph
C
Klein
Steven M
SM
Holland
Gulbu
G
Uzel
Jean-Laurent
JL
Casanova
Cindy S
CS
Ma
Stuart G
SG
Tangye
D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002454:Cell Differentiation; D019070:Cell Lineage; D006801:Humans; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000378:metabolism; D053738:Interleukin-21 Receptor alpha Subunit / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D009154:Mutation; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D050794:STAT1 Transcription Factor / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7 / Q000378:metabolism; D000098546:Interleukin-21
C508609:IL10 protein, human; C508117:IL21R protein, human; D053738:Interleukin-21 Receptor alpha Subunit; D007378:Interleukins; D050794:STAT1 Transcription Factor; C494079:STAT1 protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D050799:STAT5 Transcription Factor; D018127:Tumor Necrosis Factor Receptor Superfamily, Member 7; D016753:Interleukin-10; D000098546:Interleukin-21