RESUMEN
The CC-chemokine receptor 6 (CCR6) can be detected on naive and activated B cells. Counterintuitively, its absence accelerates the appearance of germinal centres (GCs) and increases the production of low-affinity antibodies. The detailed mechanism of CCR6 function during the humoral response has remained elusive, but previously we identified a distinct CCR6high B-cell population in vivo early after antigenic challenge. In this study, we defined this population specifically as early, activated pre-GC B cells. In accordance, we show that CCR6 is upregulated rapidly within hours on the protein or mRNA level after activation in vitro. In addition, only activated B cells migrated specifically towards CCL20, the specific ligand for CCR6. Lack of CCR6 increased the dark zone/light zone ratio of GC and led to decreased antigen-specific IgG1 and IgG2a antibody generation in a B-cell intrinsic manner in mixed bone marrow chimeras. In contrast, antigen-specific IgM responses were normal. Hence, CCR6 negatively regulates entry of activated, antigen-specific pre-GC B cells into the GC reaction.
Asunto(s)
Formación de Anticuerpos/inmunología , Linfocitos B/metabolismo , Centro Germinal/metabolismo , Receptores CCR6/metabolismo , Animales , Formación de Anticuerpos/efectos de los fármacos , Linfocitos B/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Quimiocina CCL20/farmacología , Citometría de Flujo , Centro Germinal/efectos de los fármacos , Cinética , Activación de Linfocitos/efectos de los fármacos , Ratones Endogámicos C57BL , ARN Mensajero/genética , ARN Mensajero/metabolismo , Receptores CCR6/genética , Regulación hacia Arriba/efectos de los fármacosRESUMEN
The CC-chemokine receptor 6 (CCR6) is expressed constitutively at an intermediate level on naïve B cells and is upregulated after activation on pregerminal center (GC) B cells. We hypothesized that it could be involved in the events leading to GC reaction and high-affinity antibody production, and therefore investigated the potential role of CCR6 in B-cell differentiation in vivo. After antigenic challenge of CCR6-/- mice with the T-cell-dependent antigen nitrophenyl-keyhole limpet hemocyanin (NP-KLH), GC B-cell development was found to be accelerated and the number of GC had increased significantly compared with control mice, but the antibodies produced by CCR6-/- B cells were on average of lower affinity. We conclude from these data that the CCR6/CCL20 axis has an important role in regulating the kinetics and efficiency of the GC reaction.
Asunto(s)
Linfocitos B/inmunología , Centro Germinal/inmunología , Receptores CCR6/metabolismo , Animales , Afinidad de Anticuerpos/genética , Formación de Anticuerpos/genética , Quimiocina CCL20/metabolismo , Regulación de la Expresión Génica , Centro Germinal/citología , Haptenos , Hemocianinas/inmunología , Inmunomodulación , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores CCR6/genética , Receptores CCR6/inmunología , Regulación hacia ArribaRESUMEN
B cells are known to play a dominant pathogenic role in autoimmune conditions such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. In recent times, the chemokine receptor CCR6 and its cognate ligand CCL20 have been shown to play a role in the fundamental kinetics of germinal centres and B cell responses. As CCR6 is found on B cells and is upregulated after activation, we investigated the expression of CCR6 on naive, pre-germinal centre (GC), GC/plasma cell and memory B cells in peripheral B cells of SLE patients and healthy controls using flow cytometry. Pre-germinal centre B cells are found in lower proportions and the expression of CCR6 is increased on B cells of SLE patients, suggesting a role for the chemokine pair in the pathogenesis of the disease. Further studies are needed to explore these preliminary results.