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1.
Immunity ; 55(8): 1414-1430.e5, 2022 08 09.
Artículo en Inglés | MEDLINE | ID: mdl-35896116

RESUMEN

Germinal centers (GCs), transient structures within B cell follicles and central to affinity maturation, require the coordinated behavior of T and B cells. IL-21, a pleiotropic T cell-derived cytokine, is key to GC biology through incompletely understood mechanisms. By genetically restricting production and receipt of IL-21 in vivo, we reveal how its independent actions on T and B cells combine to regulate the GC. IL-21 established the magnitude of the GC B cell response by promoting CD4+ T cell expansion and differentiation in a dose-dependent manner and with paracrine activity. Within GC, IL-21 specifically promoted B cell centroblast identity and, when bioavailability was high, plasma cell differentiation. Critically, these actions may occur irrespective of cognate T-B interactions, making IL-21 a general promoter of growth as distinct to a mediator of affinity-driven selection via synaptic delivery. This promiscuous activity of IL-21 explains the consequences of IL-21 deficiency on antibody-based immunity.


Asunto(s)
Sinapsis Inmunológicas , Linfocitos T Colaboradores-Inductores , Diferenciación Celular , Centro Germinal , Interleucinas
2.
Nat Immunol ; 17(10): 1187-96, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27487330

RESUMEN

During unresolved infections, some viruses escape immunological control and establish a persistant reservoir in certain cell types, such as human immunodeficiency virus (HIV), which persists in follicular helper T cells (TFH cells), and Epstein-Barr virus (EBV), which persists in B cells. Here we identified a specialized group of cytotoxic T cells (TC cells) that expressed the chemokine receptor CXCR5, selectively entered B cell follicles and eradicated infected TFH cells and B cells. The differentiation of these cells, which we have called 'follicular cytotoxic T cells' (TFC cells), required the transcription factors Bcl6, E2A and TCF-1 but was inhibited by the transcriptional regulators Blimp1, Id2 and Id3. Blimp1 and E2A directly regulated Cxcr5 expression and, together with Bcl6 and TCF-1, formed a transcriptional circuit that guided TFC cell development. The identification of TFC cells has far-reaching implications for the development of strategies to control infections that target B cells and TFH cells and to treat B cell-derived malignancies.


Asunto(s)
Infecciones por Arenaviridae/inmunología , Linfocitos B/inmunología , Infecciones por Virus de Epstein-Barr/inmunología , VIH/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Linfocitos T Citotóxicos/inmunología , Animales , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/metabolismo , Diferenciación Celular , Células Cultivadas , Regulación de la Expresión Génica , Centro Germinal/patología , Centro Germinal/virología , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Receptores CXCR5/genética , Receptores CXCR5/metabolismo , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
3.
EMBO Rep ; 23(9): e54677, 2022 09 05.
Artículo en Inglés | MEDLINE | ID: mdl-35801309

RESUMEN

The proliferation and differentiation of antigen-specific B cells, including the generation of germinal centers (GC), are prerequisites for long-lasting, antibody-mediated immune protection. Affinity for antigen determines B cell recruitment, proliferation, differentiation, and competitiveness in the response, largely through determining access to T cell help. However, how T cell-derived signals contribute to these outcomes is incompletely understood. Here, we report how the signature cytokine of follicular helper T cells, IL-21, acts as a key regulator of the initial B cell response by accelerating cell cycle progression and the rate of cycle entry, increasing their contribution to the ensuing GC. This effect occurs over a wide range of initial B cell receptor affinities and correlates with elevated AKT and S6 phosphorylation. Moreover, the resultant increased proliferation can explain the IL-21-mediated promotion of plasma cell differentiation. Collectively, our data establish that IL-21 acts from the outset of a T cell-dependent immune response to increase cell cycle progression and fuel cyclic re-entry of B cells, thereby regulating the initial GC size and early plasma cell output.


Asunto(s)
Centro Germinal , Linfocitos T Colaboradores-Inductores , Antígenos , Diferenciación Celular , Proliferación Celular , Interleucinas , Linfocitos T Colaboradores-Inductores/metabolismo
4.
Immunol Cell Biol ; 100(9): 705-717, 2022 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-35916066

RESUMEN

Aberrant expression of the proto-oncogene BCL6 is a driver of tumorigenesis in diffuse large B cell lymphoma (DLBCL). Mice overexpressing BCL6 from the B cell-specific immunoglobulin heavy chain µ intron promoter (Iµ-Bcl6Tg/+ ) develop B cell lymphomas with features typical of human DLBCL. While the development of B cell lymphoma in these mice is tightly controlled by T cells, the mechanisms of this immune surveillance are poorly understood. Here we show that CD4 T cells contribute to the control of lymphoproliferative disease in lymphoma-prone Iµ-Bcl6Tg/+ mice. We reveal that this CD4 T cell immuno-surveillance requires signaling by the co-stimulatory molecule CD137 ligand (CD137L; also known as 4-1BBL), which may promote the transition of pre-malignant B cells with an activated phenotype into the germinal center stage via reverse signaling, preventing their hazardous accumulation. Thus, CD137L-mediated CD4 T cell immuno-surveillance adds another layer of protection against B cell malignancy to that provided by CD8 T cell cytotoxicity.


Asunto(s)
Ligando 4-1BB , Linfoma de Células B Grandes Difuso , Ligando 4-1BB/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Centro Germinal/metabolismo , Humanos , Cadenas Pesadas de Inmunoglobulina , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/metabolismo , Linfoma de Células B Grandes Difuso/patología , Ratones , Proteínas Proto-Oncogénicas c-bcl-6/genética , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo
5.
J Immunol ; 195(3): 1006-14, 2015 Aug 01.
Artículo en Inglés | MEDLINE | ID: mdl-26101322

RESUMEN

Targeting Ags to dendritic cell (DC) surface receptors can induce a variety of responses depending on the DC type targeted, the receptor targeted, and the adjuvant used. Clec9A (DNGR-1), which is expressed by CD8(+) DCs, has been shown to bind F-actin exposed on damaged cells. Targeting Ag to this receptor in mice and nonhuman primates induces strong humoral immunity even in the absence of adjuvant, a process seen for a few select DC receptors. In contrast with other receptors, however, targeting Clec9A induces long-lived, affinity-matured Ab responses that are associated with efficient CD4(+) T cell responses shown to possess properties of follicular Th cells (TFH). In this article, we provide definitive evidence that Clec9A targeting promotes the development of TFH by showing that responding CD4 T cells express CXCR5, PD1, the TFH transcription factor Bcl6, and the cytokine IL-21, and that these cells localize to germinal centers. Furthermore, we extend studies from the model Ag OVA to the viral Ag glycoprotein D of HSV-1 and examine the capacity of primed TFH to form functional memory. We show that targeting glycoprotein D to Clec9A even in the absence of adjuvant induced long-lived memory CXCR5(+) PD1(hi) CD4(+) T cells that proliferated extensively upon secondary challenge and rapidly developed into effector TFH. This was associated with enhanced germinal center B cell responses and accelerated Ab production. Our study indicates that targeting Ags to Clec9A in the absence of adjuvant routinely generates TFH responses that form long-lived memory capable of robust secondary TFH responses.


Asunto(s)
Células Dendríticas/inmunología , Memoria Inmunológica/inmunología , Lectinas Tipo C/inmunología , Activación de Linfocitos/inmunología , Receptores Inmunológicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Traslado Adoptivo , Animales , Antígenos/inmunología , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Proteínas de Unión al ADN/biosíntesis , Centro Germinal/citología , Centro Germinal/inmunología , Subunidad alfa del Receptor de Interleucina-21/genética , Interleucinas/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ovalbúmina/inmunología , Receptor de Muerte Celular Programada 1/biosíntesis , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores CXCR5/biosíntesis , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/trasplante , Proteínas del Envoltorio Viral/inmunología
6.
Trends Immunol ; 33(6): 281-8, 2012 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-22595532

RESUMEN

The humoral immune system generates immunological memory comprising affinity matured, long-lived memory B cells and plasma cells (PCs), which are generated primarily in germinal centres (GCs). Although many factors are essential in this process, those that specifically govern B cell fate are not fully understood. The provision of T cell help to B cells is key in GC B cell fate determination, and it has become clear recently that this help involves more than direct cell-cell interactions. Recently, the cytokine interleukin (IL)-21 has been identified as a key factor that can modulate the processes within GCs and directly influence B cell fate. In this review, we examine the roles of GC cytokines in the context of cell differentiation.


Asunto(s)
Linfocitos B/inmunología , Linaje de la Célula , Centro Germinal/inmunología , Animales , Linfocitos B/citología , Comunicación Celular , Diferenciación Celular , Centro Germinal/citología , Humanos , Activación de Linfocitos
7.
J Exp Med ; 221(8)2024 Aug 05.
Artículo en Inglés | MEDLINE | ID: mdl-38842525

RESUMEN

The proliferation marker Ki67 has been attributed critical functions in maintaining mitotic chromosome morphology and heterochromatin organization during the cell cycle, indicating a potential role in developmental processes requiring rigid cell-cycle control. Here, we discovered that despite normal fecundity and organogenesis, germline deficiency in Ki67 resulted in substantial defects specifically in peripheral B and T lymphocytes. This was not due to impaired cell proliferation but rather to early lymphopoiesis at specific stages where antigen-receptor gene rearrangements occurred. We identified that Ki67 was required for normal global chromatin accessibility involving regulatory regions of genes critical for checkpoint stages in B cell lymphopoiesis. In line with this, mRNA expression of Rag1 was diminished and gene rearrangement was less efficient in the absence of Ki67. Transgenes encoding productively rearranged immunoglobulin heavy and light chains complemented Ki67 deficiency, completely rescuing early B cell development. Collectively, these results identify a unique contribution from Ki67 to somatic antigen-receptor gene rearrangement during lymphopoiesis.


Asunto(s)
Linfocitos B , Cromatina , Antígeno Ki-67 , Antígeno Ki-67/metabolismo , Animales , Cromatina/metabolismo , Cromatina/genética , Linfocitos B/metabolismo , Linfocitos B/inmunología , Linfopoyesis/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Ratones , Reordenamiento Génico , Proteínas de Homeodominio/genética , Proteínas de Homeodominio/metabolismo , Linfocitos T/metabolismo , Linfocitos T/inmunología , Ratones Endogámicos C57BL , Proliferación Celular/genética
8.
Blood ; 116(11): 1867-75, 2010 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-20538807

RESUMEN

Long-lived plasma cells in the bone marrow produce memory antibodies that provide immune protection persisting for decades after infection or vaccination but can also contribute to autoimmune and allergic diseases. However, the composition of the microenvironmental niches that are important for the generation and maintenance of these cells is only poorly understood. Here, we demonstrate that, within the bone marrow, plasma cells interact with the platelet precursors (megakaryocytes), which produce the prominent plasma cell survival factors APRIL (a proliferation-inducing ligand) and IL-6 (interleukin-6). Accordingly, reduced numbers of immature and mature plasma cells are found in the bone marrow of mice deficient for the thrombopoietin receptor (c-mpl) that show impaired megakaryopoiesis. After immunization, accumulation of antigen-specific plasma cells in the bone marrow is disturbed in these mice. Vice versa, injection of thrombopoietin allows the accumulation and persistence of a larger number of plasma cells generated in the course of a specific immune response in wild-type mice. These results demonstrate that megakaryocytes constitute an important component of the niche for long-lived plasma cells in the bone marrow.


Asunto(s)
Células de la Médula Ósea/metabolismo , Megacariocitos/metabolismo , Células Plasmáticas/metabolismo , Nicho de Células Madre/metabolismo , Animales , Células de la Médula Ósea/citología , Comunicación Celular/efectos de los fármacos , Recuento de Células , Células Cultivadas , Femenino , Citometría de Flujo , Proteínas Fluorescentes Verdes/genética , Proteínas Fluorescentes Verdes/metabolismo , Interleucina-6/genética , Interleucina-6/metabolismo , Masculino , Megacariocitos/citología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Ovalbúmina/inmunología , Ovalbúmina/farmacología , Células Plasmáticas/citología , Células Plasmáticas/efectos de los fármacos , Receptores de Trombopoyetina/genética , Receptores de Trombopoyetina/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Nicho de Células Madre/citología , Trombopoyetina/farmacología , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo
9.
Nat Commun ; 12(1): 7160, 2021 12 09.
Artículo en Inglés | MEDLINE | ID: mdl-34887406

RESUMEN

Humoral immune responses require germinal centres (GC) for antibody affinity maturation. Within GC, B cell proliferation and mutation are segregated from affinity-based positive selection in the dark zone (DZ) and light zone (LZ) substructures, respectively. While IL-21 is known to be important in affinity maturation and GC maintenance, here we show it is required for both establishing normal zone representation and preventing the accumulation of cells in the G1 cell cycle stage in the GC LZ. Cell cycle progression of DZ B cells is unaffected by IL-21 availability, as is the zone phenotype of the most highly proliferative GC B cells. Collectively, this study characterises the development of GC zones as a function of time and B cell proliferation and identifies IL-21 as an important regulator of these processes. These data help explain the requirement for IL-21 in normal antibody affinity maturation.


Asunto(s)
Linfocitos B/citología , Linfocitos B/inmunología , Ciclo Celular , Diferenciación Celular , Centro Germinal/inmunología , Animales , Proliferación Celular , Interleucinas/genética , Interleucinas/inmunología , Ratones Endogámicos C57BL , Ratones Noqueados
10.
Cell Rep ; 30(5): 1530-1541.e4, 2020 02 04.
Artículo en Inglés | MEDLINE | ID: mdl-32023467

RESUMEN

It is unknown whether the incremental increases in BCL6 amounts in antigen-activated B cells influence the unfolding differentiation before germinal center (GC) formation. By comparing shortly after immunization the distribution of conventional B cells to those enforced to express BCL6 at the upper quartile of normal and those lacking BCL6 altogether, we determined that B cell representation in the stages before the GC compartment was related to BCL6 amounts. This was not by increased proliferation or suppression of early plasmablast differentiation, but rather by preferential recruitment and progression through these early stages of B cell activation, culminating in preferential transition into GC. Once established, this bias was stable in GC over several weeks; other BCL6-regulated GC B cell behaviors were unaffected. We propose that setting BCL6 amounts very early in activated B cells will be central in determining clonal representation in the GC and thus memory populations.


Asunto(s)
Antígenos/metabolismo , Linfocitos B/metabolismo , Centro Germinal/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Animales , Proliferación Celular , Activación de Linfocitos , Ratones Endogámicos C57BL , Fenotipo , Bazo/metabolismo , Factores de Transcripción/metabolismo
11.
J Exp Med ; 215(3): 801-813, 2018 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-29386231

RESUMEN

Activated B cells can initially differentiate into three functionally distinct fates-early plasmablasts (PBs), germinal center (GC) B cells, or early memory B cells-by mechanisms that remain poorly understood. Here, we identify atypical chemokine receptor 4 (ACKR4), a decoy receptor that binds and degrades CCR7 ligands CCL19/CCL21, as a regulator of early activated B cell differentiation. By restricting initial access to splenic interfollicular zones (IFZs), ACKR4 limits the early proliferation of activated B cells, reducing the numbers available for subsequent differentiation. Consequently, ACKR4 deficiency enhanced early PB and GC B cell responses in a CCL19/CCL21-dependent and B cell-intrinsic manner. Conversely, aberrant localization of ACKR4-deficient activated B cells to the IFZ was associated with their preferential commitment to the early PB linage. Our results reveal a regulatory mechanism of B cell trafficking via an atypical chemokine receptor that shapes activated B cell fate.


Asunto(s)
Linfocitos B/citología , Linfocitos B/metabolismo , Linaje de la Célula , Receptores CCR/metabolismo , Animales , Antígenos/metabolismo , Proliferación Celular , Centro Germinal/metabolismo , Ratones Endogámicos C57BL , Bazo/citología
12.
Cell Death Differ ; 24(3): 523-533, 2017 03.
Artículo en Inglés | MEDLINE | ID: mdl-28085151

RESUMEN

The physiological role of the pro-survival BCL-2 family member A1 has been debated for a long time. Strong mRNA induction in T cells on T cell receptor (TCR)-engagement suggested a major role of A1 in the survival of activated T cells. However, the investigation of the physiological roles of A1 was complicated by the quadruplication of the A1 gene locus in mice, making A1 gene targeting very difficult. Here, we used the recently generated A1-/- mouse model to examine the role of A1 in T cell immunity. We confirmed rapid and strong induction of A1 protein in response to TCR/CD3 stimulation in CD4+ as well as CD8+ T cells. Surprisingly, on infection with the acute influenza HKx31 or the lymphocytic choriomeningitis virus docile strains mice lacking A1 did not show any impairment in the expansion, survival, or effector function of cytotoxic T cells. Furthermore, the ability of A1-/- mice to generate antigen-specific memory T cells or to provide adequate CD4-dependent help to B cells was not impaired. These results suggest functional redundancy of A1 with other pro-survival BCL-2 family members in the control of T cell-dependent immune responses.


Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Virus de la Influenza A/fisiología , Virus de la Coriomeningitis Linfocítica/fisiología , Antígenos de Histocompatibilidad Menor/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Animales , Complejo CD3/metabolismo , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Antígenos de Histocompatibilidad Menor/genética , Proteínas Proto-Oncogénicas c-bcl-2/deficiencia , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Reguladores/citología , Linfocitos T Reguladores/metabolismo
13.
J Exp Med ; 213(6): 1095-111, 2016 05 30.
Artículo en Inglés | MEDLINE | ID: mdl-27217539

RESUMEN

The generation of high-affinity antibodies requires germinal center (GC) development and differentiation of long-lived plasma cells in a multilayered process that is tightly controlled by the activity of multiple transcription factors. Here, we reveal a new layer of complexity by demonstrating that dynamic changes in Id3 and E-protein activity govern both GC and plasma cell differentiation. We show that down-regulation of Id3 in B cells is essential for releasing E2A and E2-2, which in a redundant manner are required for antigen-induced B cell differentiation. We demonstrate that this pathway controls the expression of multiple key factors, including Blimp1, Xbp1, and CXCR4, and is therefore critical for establishing the transcriptional network that controls GC B cell and plasma cell differentiation.


Asunto(s)
Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/inmunología , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/inmunología , Diferenciación Celular/inmunología , Centro Germinal/inmunología , Proteínas Inhibidoras de la Diferenciación/inmunología , Células Plasmáticas/inmunología , Animales , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción con Motivo Hélice-Asa-Hélice Básico/genética , Diferenciación Celular/genética , Proteínas Inhibidoras de la Diferenciación/genética , Ratones , Ratones Noqueados , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Receptores CXCR4/genética , Receptores CXCR4/inmunología , Factor de Transcripción 4 , Factores de Transcripción/genética , Factores de Transcripción/inmunología , Proteína 1 de Unión a la X-Box/genética , Proteína 1 de Unión a la X-Box/inmunología
14.
Nat Med ; 20(3): 283-90, 2014 Mar.
Artículo en Inglés | MEDLINE | ID: mdl-24487434

RESUMEN

Loss of function of the tumor suppressor gene PRDM1 (also known as BLIMP1) or deregulated expression of the oncogene BCL6 occurs in a large proportion of diffuse large B cell lymphoma (DLBCL) cases. However, targeted mutation of either gene in mice leads to only slow and infrequent development of malignant lymphoma, and despite frequent mutation of BCL6 in activated B cells of healthy individuals, lymphoma development is rare. Here we show that T cells prevent the development of overt lymphoma in mice caused by Blimp1 deficiency or overexpression of Bcl6 in the B cell lineage. Impairment of T cell control results in rapid development of DLBCL-like disease, which can be eradicated by polyclonal CD8(+) T cells in a T cell receptor-, CD28- and Fas ligand-dependent manner. Thus, malignant transformation of mature B cells requires mutations that impair intrinsic differentiation processes and permit escape from T cell-mediated tumor surveillance.


Asunto(s)
Linfocitos B/patología , Proteína Ligando Fas/metabolismo , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Linfocitos T/inmunología , Factores de Transcripción/genética , Animales , Linfocitos T CD8-positivos/citología , Separación Celular , Transformación Celular Neoplásica , Proteínas de Unión al ADN/metabolismo , Modelos Animales de Enfermedad , Citometría de Flujo , Genes Supresores de Tumor , Vigilancia Inmunológica/genética , Ratones , Ratones Transgénicos , Mutación , Factor 1 de Unión al Dominio 1 de Regulación Positiva , Proteínas Proto-Oncogénicas c-bcl-6 , Factores de Transcripción/fisiología
15.
J Exp Med ; 208(7): 1377-88, 2011 Jul 04.
Artículo en Inglés | MEDLINE | ID: mdl-21708925

RESUMEN

T follicular helper cells (Tfh cells) localize to follicles where they provide growth and selection signals to mutated germinal center (GC) B cells, thus promoting their differentiation into high affinity long-lived plasma cells and memory B cells. T-dependent B cell differentiation also occurs extrafollicularly, giving rise to unmutated plasma cells that are important for early protection against microbial infections. Bcl-6 expression in T cells has been shown to be essential for the formation of Tfh cells and GC B cells, but little is known about its requirement in physiological extrafollicular antibody responses. We use several mouse models in which extrafollicular plasma cells can be unequivocally distinguished from those of GC origin, combined with antigen-specific T and B cells, to show that the absence of T cell-expressed Bcl-6 significantly reduces T-dependent extrafollicular antibody responses. Bcl-6(+) T cells appear at the T-B border soon after T cell priming and before GC formation, and these cells express low amounts of PD-1. Their appearance precedes that of Bcl-6(+) PD-1(hi) T cells, which are found within the GC. IL-21 acts early to promote both follicular and extrafollicular antibody responses. In conclusion, Bcl-6(+) T cells are necessary at B cell priming to form extrafollicular antibody responses, and these pre-GC Tfh cells can be distinguished phenotypically from GC Tfh cells.


Asunto(s)
Linfocitos B/inmunología , Linfocitos B/metabolismo , Proteínas de Unión al ADN/metabolismo , Linfocitos T/inmunología , Linfocitos T/metabolismo , Animales , Formación de Anticuerpos , Linfocitos B/citología , Diferenciación Celular , Proteínas de Unión al ADN/deficiencia , Proteínas de Unión al ADN/genética , Centro Germinal/citología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Interleucinas/deficiencia , Interleucinas/metabolismo , Cooperación Linfocítica , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Células Plasmáticas/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6 , Salmonelosis Animal/inmunología , Salmonella enterica , Linfocitos T/citología , Quimera por Trasplante/inmunología , Quimera por Trasplante/metabolismo
16.
J Exp Med ; 207(2): 365-78, 2010 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-20142430

RESUMEN

Germinal centers (GCs) are sites of B cell proliferation, somatic hypermutation, and selection of variants with improved affinity for antigen. Long-lived memory B cells and plasma cells are also generated in GCs, although how B cell differentiation in GCs is regulated is unclear. IL-21, secreted by T follicular helper cells, is important for adaptive immune responses, although there are conflicting reports on its target cells and mode of action in vivo. We show that the absence of IL-21 signaling profoundly affects the B cell response to protein antigen, reducing splenic and bone marrow plasma cell formation and GC persistence and function, influencing their proliferation, transition into memory B cells, and affinity maturation. Using bone marrow chimeras, we show that these activities are primarily a result of CD3-expressing cells producing IL-21 that acts directly on B cells. Molecularly, IL-21 maintains expression of Bcl-6 in GC B cells. The absence of IL-21 or IL-21 receptor does not abrogate the appearance of T cells in GCs or the appearance of CD4 T cells with a follicular helper phenotype. IL-21 thus controls fate choices of GC B cells directly.


Asunto(s)
Linfocitos B , Diferenciación Celular , Interleucinas/inmunología , Activación de Linfocitos , Inmunidad Adaptativa , Animales , Linfocitos B/citología , Linfocitos B/inmunología , Diferenciación Celular/inmunología , Proliferación Celular , Proteínas de Unión al ADN/biosíntesis , Proteínas de Unión al ADN/inmunología , Centro Germinal/citología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Interleucinas/metabolismo , Ratones , Ratones Endogámicos C57BL , Células Plasmáticas/citología , Células Plasmáticas/inmunología , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores de Interleucina-21/inmunología , Receptores de Interleucina-21/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología
17.
J Virol ; 81(17): 9268-78, 2007 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-17567690

RESUMEN

The Sydney Blood Bank Cohort (SBBC) consists of eight blood transfusion recipients infected with nef-attenuated human immunodeficiency virus type 1 (HIV-1) acquired from a single donor. Here, we show that viral phenotypes and antibody responses differ considerably between individual cohort members, despite the single source of infection. Replication of isolated virus varied from barely detectable to similar to that of the wild-type virus, and virus isolated from five SBBC members showed coreceptor usage signatures unique to each individual. Higher viral loads and stronger neutralizing antibody responses were associated with better-replicating viral strains, and detectable viral replication was essential for the development of strong and sustained humoral immune responses. Despite the presence of strong neutralizing antibodies in a number of SBBC members, disease progression was not prevented, and each cohort member studied displayed a unique outcome of infection with nef-attenuated HIV-1.


Asunto(s)
Anticuerpos Antivirales/sangre , Productos del Gen nef/genética , Anticuerpos Anti-VIH/sangre , Infecciones por VIH/virología , Duplicado del Terminal Largo de VIH/genética , Sobrevivientes de VIH a Largo Plazo , VIH-1/genética , Transfusión Sanguínea , Recuento de Linfocito CD4 , Estudios de Cohortes , Progresión de la Enfermedad , Infecciones por VIH/inmunología , VIH-1/inmunología , VIH-1/aislamiento & purificación , VIH-1/fisiología , Humanos , Inmunoglobulina G/sangre , Pruebas de Neutralización , Fenotipo , Eliminación de Secuencia , Carga Viral , Replicación Viral , Productos del Gen nef del Virus de la Inmunodeficiencia Humana
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