Adjuvant-specific regulation of long-term antibody responses by ZBTB20.
The duration of antibody production by long-lived plasma cells varies with the type of immunization, but the basis for these differences is unknown. We demonstrate that plasma cells formed in response to the same immunogen engage distinct survival programs depending on the adjuvant. After alum-adjuvanted immunization, antigen-specific bone marrow plasma cells deficient in the transcription factor ZBTB20 failed to accumulate over time, leading to a progressive loss of antibody production relative to wild-type controls. Fetal liver reconstitution experiments demonstrated that the requirement for ZBTB20 was B cell intrinsic. No defects were observed in germinal center numbers, affinity maturation, or plasma cell formation or proliferation in ZBTB20-deficient chimeras. However, ZBTB20-deficient plasma cells expressed reduced levels of MCL1 relative to wild-type controls, and transgenic expression of BCL2 increased serum antibody titers. These data indicate a role for ZBTB20 in promoting survival in plasma cells. Strikingly, adjuvants that activate TLR2 and TLR4 restored long-term antibody production in ZBTB20-deficient chimeras through the induction of compensatory survival programs in plasma cells. Thus, distinct lifespans are imprinted in plasma cells as they are formed, depending on the primary activation conditions. The durability of vaccines may accordingly be improved through the selection of appropriate adjuvants.
Department of Pathology and Immunology, Washington University in St. Louis School of Medicine, St. Louis, MO 63110.
Yinan
Y
Wang
Deepta
D
Bhattacharya
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000534:Alum Compounds; D000818:Animals; D000911:Antibodies, Monoclonal; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology*; D001973:Bromodeoxyuridine; D002470:Cell Survival / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D018076:DNA, Complementary; D004797:Enzyme-Linked Immunosorbent Assay; D058501:Enzyme-Linked Immunospot Assay; D005455:Fluorescent Antibody Technique; D005838:Genotype; D006241:Haptens; D008099:Liver / Q000166:cytology / Q000276:immunology; D051379:Mice; D046228:Microarray Analysis; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000378:metabolism; D010950:Plasma Cells / Q000187:drug effects / Q000276:immunology*; D060888:Real-Time Polymerase Chain Reaction; D018709:Statistics, Nonparametric; D014157:Transcription Factors / Q000172:deficiency / Q000276:immunology*
D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D000911:Antibodies, Monoclonal; D017931:DNA Primers; D018076:DNA, Complementary; D006241:Haptens; C579094:Mcl1 protein, mouse; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D014157:Transcription Factors; C520426:Zbtb20 protein, mouse; C041524:aluminum sulfate; D001973:Bromodeoxyuridine