RESUMEN
Interleukin 17 (IL-17) is a cytokine associated with inflammation, autoimmunity and defense against some bacteria. Here we show that IL-17 can promote autoimmune disease through a mechanism distinct from its proinflammatory effects. As compared with wild-type mice, autoimmune BXD2 mice express more IL-17 and show spontaneous development of germinal centers (GCs) before they increase production of pathogenic autoantibodies. We show that blocking IL-17 signaling disrupts CD4+ T cell and B cell interactions required for the formation of GCs and that mice lacking the IL-17 receptor have reduced GC B cell development and humoral responses. Production of IL-17 correlates with upregulated expression of the genes Rgs13 and Rgs16, which encode regulators of G-protein signaling, and results in suppression of the B cell chemotactic response to the chemokine CXCL12. These findings suggest a mechanism by which IL-17 drives autoimmune responses by promoting the formation of spontaneous GCs.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Centro Germinal/inmunología , Interleucina-17/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Quimiotaxis de Leucocito/inmunología , Interleucina-17/antagonistas & inhibidores , Ratones , Ratones Mutantes , Receptores de Interleucina-17/genética , Receptores de Interleucina-17/metabolismoRESUMEN
Although it is clear that the loss of CD4(+) T cells is a predisposing factor for the development of Pneumocystis pneumonia, specific Th mechanisms mediating protection are not well understood. Th1, Th2, and Th17 responses have each been implicated in protective responses during infection. As STAT4 may promote Th1 and Th17 development, yet antagonize Th2 development, we investigated its role in Pneumocystis murina host defense. STAT4 was required for Th1 and, unexpectedly, Th2 responses in the lungs of C57BL/6 (BL/6) and BALB/c mice 14 d postchallenge, but only BALB/c Stat4(-/-) mice demonstrated susceptibility to P. murina lung infection. BL/6 Stat4(-/-), but not BALB/c Stat4(-/-), mice maintained an enhanced alternatively activated (M2) macrophage signature in the lungs, which we have previously reported to be associated with enhanced P. murina clearance. In addition, anti-P. murina class-switched Abs were increased in BL/6 Stat4(-/-) mice, but not BALB/c Stat4(-/-) mice. Supporting our experimental observations, plasma from HIV-infected individuals colonized with Pneumocystis jirovecii contained significantly lower levels of the Th2 cytokines IL-4, IL-5, and IL-13 compared with HIV-infected individuals who were not colonized. Collectively, our data suggest that robust local and systemic Th2-mediated responses are critical for immunity to Pneumocystis.
Asunto(s)
Infecciones por VIH/complicaciones , Neumonía por Pneumocystis/inmunología , Factor de Transcripción STAT4/inmunología , Células Th2/inmunología , Animales , Citocinas/sangre , Ensayo de Inmunoadsorción Enzimática , Infecciones por VIH/inmunología , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Neumonía por Pneumocystis/complicaciones , Reacción en Cadena en Tiempo Real de la PolimerasaRESUMEN
CD19-deficient mice were used as a model to study follicular dendritic cell (FDC) activation because these mice have normal numbers of FDC-containing primary follicles, but lack the ability to activate FDCs or form GCs. It was hypothesized that CD19 expression is necessary for B-cell activation and upregulation of membrane lymphotoxin (mLT) expression, which promotes FDC activation. Using VCAM-1 and FcγRII/III as FDC activation markers, it was determined that the adoptive transfer of CD19(+) wild-type B cells into CD19-deficient hosts rescued GC formation and FDC activation, demonstrating that CD19 expression on B cells is required for FDC activation. In contrast, CD19(+) donor B cells lacking mLT were unable to induce VCAM-1 expression on FDCs, furthermore FcγRII/III upregulation was impaired in FDCs stimulated with mLT-deficient B cells. VCAM-1 expression on FDCs, but not FcγRII/III, was rescued when CD19-deficient B cells expressing transgenic mLT were cotransferred into recipient mice with CD19(+) , mLT-deficient B cells, suggesting that FDC activation requires the CD19-dependent upregulation of mLT on activated B cells. Collectively, these data demonstrate that activated B cells are responsible for the initiation of FDC activation resulting in a microenvironment supportive of GC development and maintenance.
Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Células Dendríticas Foliculares/inmunología , Células Dendríticas Foliculares/metabolismo , Centro Germinal/inmunología , Centro Germinal/metabolismo , Heterotrímero de Linfotoxina alfa1 y beta2/biosíntesis , Animales , Antígenos CD19/biosíntesis , Antígenos CD19/genética , Antígenos CD19/inmunología , Activación de Linfocitos , Heterotrímero de Linfotoxina alfa1 y beta2/genética , Heterotrímero de Linfotoxina alfa1 y beta2/inmunología , Ratones , Ratones Endogámicos C57BL , Receptores de IgG/biosíntesis , Receptores de IgG/genética , Receptores de IgG/inmunología , Regulación hacia Arriba , Molécula 1 de Adhesión Celular Vascular/biosíntesis , Molécula 1 de Adhesión Celular Vascular/genética , Molécula 1 de Adhesión Celular Vascular/inmunologíaRESUMEN
The marginal zone (MZ) of the mouse spleen contains macrophages that express receptors that trap pathogens, including the scavenger receptor macrophage receptor with a collagenous structure and the C-type lectin specific intracellular adhesion molecule-grabbing nonintegrin receptor 1 (SIGN-R1). We previously reported that expression of SIGN-R1 was decreased in CD19-deficient mice. In this study, we demonstrate that SIGN-R1 is expressed on a subset of macrophage receptor with a collagenous structure (MARCO)(+) macrophages. This subset is diminished when MZ B cells are absent due to either genetic developmental defects or following transient migration of B cells out of the MZ. When B cells return to the MZ, there is a delay in recovery of SIGN-R1-expressing macrophages. During this period, capture of Ficoll, which for the macrophages requires SIGN-R1, remains defective not only by the macrophages, but also by the B cells. Thus, MZ B cells regulate expression of molecules on macrophages that are important for trapping Ag, which, in turn, is required for Ag capture by the B cells.
Asunto(s)
Antígenos/metabolismo , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Macrófagos/citología , Macrófagos/inmunología , Bazo/citología , Bazo/inmunología , Animales , Antígenos/genética , Antígenos CD19/genética , Subgrupos de Linfocitos B/metabolismo , Moléculas de Adhesión Celular/deficiencia , Moléculas de Adhesión Celular/genética , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Movimiento Celular/genética , Movimiento Celular/inmunología , Lectinas Tipo C/deficiencia , Lectinas Tipo C/genética , Macrófagos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Receptores de Superficie Celular/deficiencia , Receptores de Superficie Celular/genética , Bazo/metabolismoRESUMEN
Follicular dendritic cells (FDCs) are essential for high-affinity antibody production and for the development of B cell memory. Historically, FDCs have been characterized as 'accessory' cells that passively support germinal centre (GC) responses. However, recent observations suggest that FDCs actively shape humoral immunity. In this Review, we discuss recent findings concerning the antigen acquisition and retention functions of FDCs, and relevant implications for protective immunity. Furthermore, we describe the roles of FDCs within GCs in secondary lymphoid organs and discuss FDC development within this dynamic environment. Finally, we discuss how a better understanding of FDCs could facilitate the design of next-generation vaccines.
Asunto(s)
Formación de Anticuerpos/inmunología , Presentación de Antígeno/inmunología , Células Dendríticas Foliculares/inmunología , Anticuerpos/inmunología , Afinidad de Anticuerpos/inmunología , Complejo Antígeno-Anticuerpo/inmunología , Antígenos/inmunología , Linfocitos B/inmunología , Células Dendríticas Foliculares/citología , Células Dendríticas Foliculares/virología , VIH/inmunología , Humanos , Receptores de Quimiocina/inmunología , Transducción de Señal/inmunología , Linfocitos T/inmunologíaRESUMEN
The germinal center is a critical locus in the production of protective immunity, but its function is poorly understood. Studies of mutant forms of CD19 revealed differences in signaling in different compartments inside the germinal center, and structural findings indicate a selective role in the interaction with follicular dendritic cells in the GC. Loss of these signals leads to surprising changes in germinal center B cells that challenge previous models of GC function.