International Immunology, Vol. 15, No. 4, pp. 457-466,
April 2003
© 2003 Japanese Society for Immunology
FEATURED ARTICLE OF THE MONTH |
Human germinal center B cells differ from naive and memory B cells by their aggregated MHC class II-rich compartments lacking HLA-DO
1 Baylor Institute for Immunology Research, Dallas, TX 75204, USA 2 Basel Institute for Immunology, 4070 Basel, Switzerland 3 Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA 4 Present address: Roche Center for Medical Genomics, Hoffmann-La Roche, 4070 Basel, Switzerland 5 Present address: Généthon-CNRS UMR 8115, 91002 Evry Cedex, France
Correspondence to: V. Pascual, Baylor Institute for Immunology Research, 3434 Live Oak, Dallas, TX 75204, USA. E-mail: virginip{at}baylorhealth.edu and J. Davoust, Généthon-CNRS UMR 8115, 1 bis rue de l’Internationale, 91002 Evry Cedex, France. E-mail: davoust{at}genethon.fr
Transmitting editor: M. Nussenzweig
To generate memory B cells bearing high-affinity antibodies, naive B cells first encounter antigen in the T cell-rich areas of secondary lymphoid organs. There, they are activated by antigen-specific T cells and become germinal center (GC) founder B cells. GC founders enter the GC to become centroblasts that proliferate and mutate their BCR. Centroblasts differentiate into centrocytes that undergo selection, which requires both the recognition/capture of antigen on follicular dendritic cells and the presentation of processed antigen to GC T cells. Because at each stage of differentiation B cells act as antigen-presenting cells, we analyzed their content of HLA-DR+-rich compartments (MIIC), as well as their expression of HLA-DM, which catalyzes peptide loading of class II molecules, and HLA-DO, which interacts with HLA-DM and focuses MHC class II peptide loading on antigens internalized by the BCR. Naive and memory B cells concentrate HLA-DR, -DM and -DO into compartments dispersed under the cell surface, which are identified by their expression of lysosome-associated membrane protein (Lamp)-1 as late endosomes/lysosomes. GC founders and GC B cells express larger Lamp-1+DR+ compartments that are concentrated in the juxta-nuclear region. These compartments express lower levels of HLA-DM and virtually no HLA-DO. Upon induction of a GC founder phenotype through the prolonged (days) co-ligation of BCR and CD40, the naive B cell’s peripheral DR+DM+Lamp-1+ compartments aggregate in a polar fashion close to the nucleus. Furthermore, HLA-DO expression virtually disappears, whereas low levels of HLA-DM remain co-localized with HLA-DR. Anti-
/
antibodies, used as surrogate antigens, are promptly (minutes) endocytosed in naive, memory and GC B cells. Then, naive and memory B cells target the surrogate antigen to their peripheral HLA-DO+ MIIC, while GC B cells target it to their HLA-DO– MIIC aggregates. Taken together, our results show that human GC B cells differ from naive and memory B cells by their aggregated MIIC that lack HLA-DO.
Keywords: germinal center, HLA-DM, HLA-DO, HLA-DR, human B cell subsets
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