Memory, but not naive, peripheral blood B lymphocytes differentiate into Ig-secreting cells after CD40 ligation and costimulation with IL-4 and the differentiation factors IL-2, IL-10, and IL-3.
The ligation of CD40 on B lymphocytes by CD40 ligand, transiently expressed on activated Th cells, provides a key activation signal required for the germinal center B cell response. In vitro, human B cell activation has been investigated extensively by coculturing tonsillar B cells with CD32-transfected fibroblasts coated with anti-CD40 Abs, in the presence of cytokines (the CD40 system). When tonsillar IgD+ B cells are cultured in the CD40 system with IL-4, cells proliferate and switch to IgG, but they display a block of differentiation illustrated by the persistence of IgD expression on cycling B cells. In this study, we analyzed the responses of peripheral blood B lymphocyte fractions, which may contain fewer in vivo activated cells than those from tonsils. While the differentiation block was confirmed with peripheral naive B cells cultured in the CD40 system with IL-4, it was also observed with the combination of IL-2, IL-10, and IL-3 alone or together with IL-4 (persistence of >90% IgD+ cells, including 24-60% IgD+, IgG+ cells, and <6% IgD+, IgA+ cells after 8 days). IgD+, IgG-, and IgA- (naive) B cells secreted 70-fold less Ig than IgG+, IgA+ (memory) B cells in response to anti-CD40 plus IL-2, IL-10, and IL-3. IgG-, IgA- B cells, or IgD-, IgM+, which should include IgM+ memory cells, strongly secreted IgM, but no IgG. In conclusion, only memory B cells secreted Ig; like memory T cells, their activation requirements to differentiate into effector cells seem less stringent than those of the naive cells.
Kindler
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Division of Hematology, Geneva University Hospital, Switzerland. vincent-kindler@hcuge.ch
Zubler
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RH
D000917:Antibody Formation; D001402:B-Lymphocytes / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D019013:CD40 Antigens / Q000276:immunology*; D002454:Cell Differentiation / Q000187:drug effects; D006801:Humans; D017578:Immunoglobulin Class Switching / Q000187:drug effects / Q000502:physiology; D007136:Immunoglobulins / Q000096:biosynthesis / Q000145:classification; D007156:Immunologic Memory; D016753:Interleukin-10 / Q000494:pharmacology; D007376:Interleukin-2 / Q000494:pharmacology; D007377:Interleukin-3 / Q000494:pharmacology; D015847:Interleukin-4 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology*; D008213:Lymphocyte Activation; D014066:Palatine Tonsil / Q000166:cytology
D019013:CD40 Antigens; D007136:Immunoglobulins; D007376:Interleukin-2; D007377:Interleukin-3; D007378:Interleukins; D016753:Interleukin-10; D015847:Interleukin-4