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1.
J Exp Med ; 215(4): 1227-1243, 2018 04 02.
Artigo em Inglês | MEDLINE | ID: mdl-29549115

RESUMO

Germinal centers (GCs) are the sites where B cells undergo affinity maturation. The regulation of cellular output from the GC is not well understood. Here, we show that from the earliest stages of the GC response, plasmablasts emerge at the GC-T zone interface (GTI). We define two main factors that regulate this process: Tfh-derived IL-21, which supports production of plasmablasts from the GC, and TNFSF13 (APRIL), which is produced by a population of podoplanin+ CD157high fibroblastic reticular cells located in the GTI that are also rich in message for IL-6 and chemokines CXCL12, CCL19, and CCL21. Plasmablasts in the GTI express the APRIL receptor TNFRSF13B (TACI), and blocking TACI interactions specifically reduces the numbers of plasmablasts appearing in the GTI. Plasma cells generated in the GTI may provide an early source of affinity-matured antibodies that may neutralize pathogens or provide feedback regulating GC B cell selection.


Assuntos
Centro Germinativo/citologia , Plasmócitos/metabolismo , Transdução de Sinais , Células Estromais/citologia , Linfócitos T Auxiliares-Indutores/citologia , Animais , Antígenos/metabolismo , Diferenciação Celular , Movimento Celular , Quimiocinas/metabolismo , Regulação da Expressão Gênica , Imunidade , Fatores Reguladores de Interferon/metabolismo , Interleucinas/genética , Interleucinas/metabolismo , Ligantes , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Células Estromais/metabolismo , Linfócitos T Auxiliares-Indutores/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismo , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/metabolismo
2.
J Exp Med ; 210(3): 457-64, 2013 Mar 11.
Artigo em Inglês | MEDLINE | ID: mdl-23420879

RESUMO

Affinity maturation of B cells in germinal centers (GCs) is a process of evolution, involving random mutation of immunoglobulin genes followed by natural selection by T cells. Only B cells that have acquired antigen are able to interact with T cells. Antigen acquisition is dependent on the interaction of B cells with immune complexes inside GCs. It is not clear how efficient selection of B cells is maintained while their affinity matures. Here we show that the B cells' own secreted products, antibodies, regulate GC selection by limiting antigen access. By manipulating the GC response with monoclonal antibodies of defined affinities, we show that antibodies in GCs are in affinity-dependent equilibrium with antibodies produced outside and that restriction of antigen access influences B cell selection, seen as variations in apoptosis, plasma cell output, T cell interaction, and antibody affinity. Feedback through antibodies produced by GC-derived plasma cells can explain how GCs maintain an adequate directional selection pressure over a large range of affinities throughout the course of an immune response, accelerating the emergence of B cells of highest affinities. Furthermore, this mechanism may explain how spatially separated GCs communicate and how the GC reaction terminates.


Assuntos
Anticorpos/imunologia , Linfócitos B/imunologia , Linhagem da Célula , Centro Germinativo/imunologia , Animais , Afinidade de Anticorpos , Linfócitos B/citologia , Células Dendríticas Foliculares/imunologia , Camundongos , Camundongos Endogâmicos C57BL
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