The hierarchical process of differentiation of long-lived antibody-secreting cells is dependent on integrated signals derived from antigen and IL-17A.
Switched CD19-positive memory B cells purified from mice with chronic immune response against Thalassophrynenattereri venom proteins were cultured with venom or cytokines. Our results confirm the existence of a hierarchic process of differentiation: activated memory B cells progressively acquire increasing levels of CD138 and decreasing levels of CD45R/B220 to finally arrive at ASC with B220(neg) phenotype, which are IgG1-secreting cells. Only Bmem from peritoneal cavity or bone marrow of VTn immunized mice presented the capacity to generate ASC functionally active. IL-17A or IL-21/IL-23/IL-33 improves the ability of venom to induce intracellular IgG of peritoneal derived-ASC. Cognate stimulation with venom and IL-17A is sufficient to down-regulate the expression of CD45R/B220. BAFF-R is up-regulated in splenic or medullar derived-ASC stimulated by venom, CpG or cytokines. Only splenic derived-ASC up-regulate Bcl-2 expression after CpG or the combination of IL-21/IL-23/IL-33 stimulation. Finally, the activation of ASC for IgG1 secretion is triggered by venom proteins in peritoneal cavity and by IL-17A in medullar niche. These results show the importance of the integration of signals downstream of BCR and IL17-A receptors in modulating ASC differentiation, focusing in the microenvironment niche of their generation.
Immunoregulation Unit, Special Laboratory of Applied Toxinology (CEPID/FAPESP), Butantan Institute and Department of Immunology, University of São Paulo, São Paulo, Brazil.
Lidiane Zito
LZ
Grund
Monica
M
Lopes-Ferreira
Carla
C
Lima
D000818:Animals; D000921:Antibody-Producing Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D000941:Antigens / Q000276:immunology*; D018941:Antigens, CD19 / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D053265:B-Cell Activation Factor Receptor / Q000378:metabolism; D001402:B-Lymphocytes / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology*; D002462:Cell Membrane / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D005397:Fish Venoms / Q000276:immunology; D007074:Immunoglobulin G / Q000096:biosynthesis; D007156:Immunologic Memory / Q000187:drug effects; D020381:Interleukin-17 / Q000378:metabolism*; D053759:Interleukin-23 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology; D017493:Leukocyte Common Antigens / Q000378:metabolism; D018655:Lymphocyte Count; D008297:Male; D051379:Mice; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013154:Spleen / Q000166:cytology; D051217:Toll-Like Receptor 9 / Q000378:metabolism; D000098546:Interleukin-21
D000941:Antigens; D018941:Antigens, CD19; D053265:B-Cell Activation Factor Receptor; D005397:Fish Venoms; D007074:Immunoglobulin G; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D019253:Proto-Oncogene Proteins c-bcl-2; D011994:Recombinant Proteins; C495370:Tlr9 protein, mouse; D051217:Toll-Like Receptor 9; D017493:Leukocyte Common Antigens; D000098546:Interleukin-21