IL-21 acts directly on B cells to regulate Bcl-6 expression and germinal center responses.
During T cell-dependent responses, B cells can either differentiate extrafollicularly into short-lived plasma cells or enter follicles to form germinal centers (GCs). Interactions with T follicular helper (Tfh) cells are required for GC formation and for selection of somatically mutated GC B cells. Interleukin (IL)-21 has been reported to play a role in Tfh cell formation and in B cell growth, survival, and isotype switching. To date, it is unclear whether the effect of IL-21 on GC formation is predominantly a consequence of this cytokine acting directly on the Tfh cells or if IL-21 directly influences GC B cells. We show that IL-21 acts in a B cell-intrinsic fashion to control GC B cell formation. Mixed bone marrow chimeras identified a significant B cell-autonomous effect of IL-21 receptor (R) signaling throughout all stages of the GC response. IL-21 deficiency profoundly impaired affinity maturation and reduced the proportion of IgG1(+) GC B cells but did not affect formation of early memory B cells. IL-21R was required on GC B cells for maximal expression of Bcl-6. In contrast to the requirement for IL-21 in the follicular response to sheep red blood cells, a purely extrafollicular antibody response to Salmonella dominated by IgG2a was intact in the absence of IL-21.
Linterman
Michelle A
MA
John Curtin School of Medical Research, Australian National University, Canberra, ACT 2601, Australia.
Beaton
Laura
L
Yu
Di
D
Ramiscal
Roybel R
RR
Srivastava
Monika
M
Hogan
Jennifer J
JJ
Verma
Naresh K
NK
Smyth
Mark J
MJ
Rigby
Robert J
RJ
Vinuesa
Carola G
CG
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D002450:Cell Communication / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D004268:DNA-Binding Proteins / Q000096:biosynthesis* / Q000276:immunology; D018858:Germinal Center / Q000166:cytology / Q000276:immunology*; D007132:Immunoglobulin Isotypes / Q000096:biosynthesis / Q000235:genetics; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D051560:Proto-Oncogene Proteins c-bcl-6; D053655:Receptors, Interleukin-21 / Q000276:immunology / Q000378:metabolism; D012756:Sheep; D015398:Signal Transduction / Q000276:immunology; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology; D000098546:Interleukin-21
C490010:Bcl6 protein, mouse; D004268:DNA-Binding Proteins; D007132:Immunoglobulin Isotypes; D007378:Interleukins; D051560:Proto-Oncogene Proteins c-bcl-6; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21