IL-21 regulates germinal center B cell differentiation and proliferation through a B cell-intrinsic mechanism.
Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.
The Walter and Eliza Hall Institute of Medical Research, Parkville 3052, Australia.
Dimitra
D
Zotos
Jonathan M
JM
Coquet
Yang
Y
Zhang
Amanda
A
Light
Kathy
K
D'Costa
Axel
A
Kallies
Lynn M
LM
Corcoran
Dale I
DI
Godfrey
Kai-Michael
KM
Toellner
Mark J
MJ
Smyth
Stephen L
SL
Nutt
David M
DM
Tarlinton
D056704:Adaptive Immunity; D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D007378:Interleukins / Q000276:immunology* / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D010950:Plasma Cells / Q000166:cytology / Q000276:immunology; D051560:Proto-Oncogene Proteins c-bcl-6; D053655:Receptors, Interleukin-21 / Q000276:immunology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D000098546:Interleukin-21
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21