Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 17 de 17
Filtrar
1.
Nat Immunol ; 24(8): 1345-1357, 2023 08.
Artículo en Inglés | MEDLINE | ID: mdl-37400675

RESUMEN

CD4+ T cells play key roles in a range of immune responses, either as direct effectors or through accessory cells, including CD8+ T lymphocytes. In cancer, neoantigen (NeoAg)-specific CD8+ T cells capable of direct tumor recognition have been extensively studied, whereas the role of NeoAg-specific CD4+ T cells is less well understood. We have characterized the murine CD4+ T cell response against a validated NeoAg (CLTCH129>Q) expressed by the MHC-II-deficient squamous cell carcinoma tumor model (SCC VII) at the level of single T cell receptor (TCR) clonotypes and in the setting of adoptive immunotherapy. We find that the natural CLTCH129>Q-specific repertoire is diverse and contains TCRs with distinct avidities as measured by tetramer-binding assays and CD4 dependence. Despite these differences, CD4+ T cells expressing high or moderate avidity TCRs undergo comparable in vivo proliferation to cross-presented antigen from growing tumors and drive similar levels of therapeutic immunity that is dependent on CD8+ T cells and CD40L signaling. Adoptive cellular therapy (ACT) with NeoAg-specific CD4+ T cells is most effective when TCR-engineered cells are differentiated ex vivo with IL-7 and IL-15 rather than IL-2 and this was associated with both increased expansion as well as the acquisition and stable maintenance of a T stem cell memory (TSCM)-like phenotype in tumor-draining lymph nodes (tdLNs). ACT with TSCM-like CD4+ T cells results in lower PD-1 expression by CD8+ T cells in the tumor microenvironment and an increased frequency of PD-1+CD8+ T cells in tdLNs. These findings illuminate the role of NeoAg-specific CD4+ T cells in mediating antitumor immunity via providing help to CD8+ T cells and highlight their therapeutic potential in ACT.


Asunto(s)
Linfocitos T CD8-positivos , Neoplasias , Ratones , Animales , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Inmunoterapia Adoptiva , Inmunoterapia , Linfocitos T CD4-Positivos , Células Madre , Microambiente Tumoral
3.
Immunity ; 52(5): 842-855.e6, 2020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32353250

RESUMEN

B cell subsets expressing the transcription factor T-bet are associated with humoral immune responses and autoimmunity. Here, we examined the anatomic distribution, clonal relationships, and functional properties of T-bet+ and T-bet- memory B cells (MBCs) in the context of the influenza-specific immune response. In mice, both T-bet- and T-bet+ hemagglutinin (HA)-specific B cells arose in germinal centers, acquired memory B cell markers, and persisted indefinitely. Lineage tracing and IgH repertoire analyses revealed minimal interconversion between T-bet- and T-bet+ MBCs, and parabionts showed differential tissue residency and recirculation properties. T-bet+ MBCs could be subdivided into recirculating T-betlo MBCs and spleen-resident T-bethi MBCs. Human MBCs displayed similar features. Conditional gene deletion studies revealed that T-bet expression in B cells was required for nearly all HA stalk-specific IgG2c antibodies and for durable neutralizing titers to influenza. Thus, T-bet expression distinguishes MBC subsets that have profoundly different homing, residency, and functional properties, and mediate distinct aspects of humoral immune memory.


Asunto(s)
Especificidad de Anticuerpos/inmunología , Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Memoria Inmunológica/inmunología , Especificidad de Órganos/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Centro Germinal/citología , Centro Germinal/inmunología , Centro Germinal/metabolismo , Anticuerpos Anti-VIH/inmunología , Humanos , Virus de la Influenza A/inmunología , Virus de la Influenza A/fisiología , Gripe Humana/inmunología , Gripe Humana/virología , Ratones , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismo
4.
Immunol Rev ; 269(1): 118-29, 2016 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-26683149

RESUMEN

A subset of B cells with unique phenotypic and functional features-termed Age-associated B cells (ABCs)-has recently been identified in both mice and humans. These cells are characterized by a T-BET driven transcriptional program, robust responsiveness to TLR7 and TLR9 ligands, and a propensity for IgG2a/c production. Beyond their age-related accumulation, these cells play roles in both normal and pathogenic humoral immune responses regardless of host age. Thus, B cells with the ABC phenotype and transcriptional signature appear during viral, bacterial, and parasitic infections, but also arise during humoral autoimmune disease in both mouse models and humans. These observations suggest that both autoantigens and certain classes of pathogens provide the signals required for ABC differentiation. Herein, we review the discovery and features of ABCs, and propose that they are a memory subset generated by nucleic acid-containing antigens in the context of a promoting inflammatory cytokine milieu.


Asunto(s)
Envejecimiento/inmunología , Enfermedades Autoinmunes/inmunología , Subgrupos de Linfocitos B/fisiología , Linfocitos B/fisiología , Infecciones/inmunología , Animales , Diferenciación Celular , Citocinas/metabolismo , Humanos , Inmunoglobulina G/metabolismo , Ratones , Ácidos Nucleicos/inmunología , Proteínas de Dominio T Box/metabolismo , Receptor Toll-Like 7/metabolismo , Receptor Toll-Like 9/metabolismo
5.
J Immunol ; 198(5): 1921-1927, 2017 03 01.
Artículo en Inglés | MEDLINE | ID: mdl-28093524

RESUMEN

The origin and nature of age-associated B cells (ABCs) in mice are poorly understood. In this article, we show that their emergence required MHC class II and CD40/CD40L interactions. Young donor B cells were adoptively transferred into congenic recipients and allowed to remain for 1 mo in the absence of external Ag. B cells expressing the T-bet transcription factor, a marker for ABCs, were generated after multiple cell divisions from C57BL/6 donors but not from MHC class II- or CD40-deficient donors. Furthermore, old CD154 (CD40L)-deficient mice did not accrue ABCs, confirming that they arise primarily through T-dependent interactions. To determine what Igs ABCs express, we sequenced VH and Vκ rearranged genes from unimmunized 22-mo-old C57BL/6 mice and showed that they had a heterogeneous repertoire, which was comparable to that seen in old follicular and marginal zone B cell subsets. However, in contrast to the follicular and marginal zone cells, ABCs displayed significant somatic hypermutation. The mutation frequency was lower than found in germinal center cells after deliberate immunization, suggesting that ABCs have undergone mild stimulation from endogenous Ags over time. These observations show that quiescent ABCs are Ag-experienced cells that accumulate during T cell-dependent responses to diverse Ags during the life of an individual.


Asunto(s)
Envejecimiento/inmunología , Subgrupos de Linfocitos B/inmunología , Anticuerpos de Dominio Único/genética , Hipermutación Somática de Inmunoglobulina , Animales , Subgrupos de Linfocitos B/metabolismo , Antígenos CD40/deficiencia , Antígenos CD40/inmunología , Reordenamiento Génico , Genes MHC Clase II , Centro Germinal/inmunología , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Análisis de Secuencia de ADN
6.
J Immunol ; 197(4): 1023-8, 2016 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-27430719

RESUMEN

T-bet and CD11c expression in B cells is linked with IgG2c isotype switching, virus-specific immune responses, and humoral autoimmunity. However, the activation requisites and regulatory cues governing T-bet and CD11c expression in B cells remain poorly defined. In this article, we reveal a relationship among TLR engagement, IL-4, IL-21, and IFN-γ that regulates T-bet expression in B cells. We find that IL-21 or IFN-γ directly promote T-bet expression in the context of TLR engagement. Further, IL-4 antagonizes T-bet induction. Finally, IL-21, but not IFN-γ, promotes CD11c expression independent of T-bet. Using influenza virus and Heligmosomoides polygyrus infections, we show that these interactions function in vivo to determine whether T-bet(+) and CD11c(+) B cells are formed. These findings suggest that T-bet(+) B cells seen in health and disease share the common initiating features of TLR-driven activation within this circumscribed cytokine milieu.


Asunto(s)
Linfocitos B/inmunología , Antígeno CD11c/inmunología , Activación de Linfocitos/inmunología , Transducción de Señal/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Linfocitos B/metabolismo , Antígeno CD11c/biosíntesis , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Regulación de la Expresión Génica/inmunología , Humanos , Interferón gamma/inmunología , Interferón gamma/metabolismo , Interleucina-4/inmunología , Interleucina-4/metabolismo , Interleucinas/inmunología , Interleucinas/metabolismo , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Noqueados , Reacción en Cadena de la Polimerasa , Proteínas de Dominio T Box/biosíntesis , Receptores Toll-Like/inmunología
7.
J Immunol ; 195(7): 3449-62, 2015 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-26320247

RESUMEN

The HuR RNA-binding protein posttranscriptionally controls expression of genes involved in cellular survival, proliferation, and differentiation. To determine roles of HuR in B cell development and function, we analyzed mice with B lineage-specific deletion of the HuR gene. These HuRΔ/Δ mice have reduced numbers of immature bone marrow and mature splenic B cells, with only the former rescued by p53 inactivation, indicating that HuR supports B lineage cells through developmental stage-specific mechanisms. Upon in vitro activation, HuRΔ/Δ B cells have a mild proliferation defect and impaired ability to produce mRNAs that encode IgH chains of secreted Abs, but no deficiencies in survival, isotype switching, or expression of germinal center (GC) markers. In contrast, HuRΔ/Δ mice have minimal serum titers of all Ab isotypes, decreased numbers of GC and plasma B cells, and few peritoneal B-1 B cells. Moreover, HuRΔ/Δ mice have severely decreased GCs, T follicular helper cells, and high-affinity Abs after immunization with a T cell-dependent Ag. This failure of HuRΔ/Δ mice to mount a T cell-dependent Ab response contrasts with the ability of HuRΔ/Δ B cells to become GC-like in vitro, indicating that HuR is essential for aspects of B cell activation unique to the in vivo environment. Consistent with this notion, we find in vitro stimulated HuRΔ/Δ B cells exhibit modestly reduced surface expression of costimulatory molecules whose expression is similarly decreased in humans with common variable immunodeficiency. HuRΔ/Δ mice provide a model to identify B cell-intrinsic factors that promote T cell-dependent immune responses in vivo.


Asunto(s)
Linfocitos B/inmunología , Proteína 1 Similar a ELAV/biosíntesis , Activación de Linfocitos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Linfocitos B/citología , Células de la Médula Ósea/inmunología , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Proliferación Celular/genética , Proteína 1 Similar a ELAV/genética , Centro Germinal/inmunología , Cadenas Pesadas de Inmunoglobulina/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Procesamiento Postranscripcional del ARN/genética , ARN Mensajero/biosíntesis , Proteína p53 Supresora de Tumor/genética
8.
Sci Transl Med ; 16(736): eabj9905, 2024 Feb 28.
Artículo en Inglés | MEDLINE | ID: mdl-38416845

RESUMEN

The clinical impact of tumor-specific neoantigens as both immunotherapeutic targets and biomarkers has been impeded by the lack of efficient methods for their identification and validation from routine samples. We have developed a platform that combines bioinformatic analysis of tumor exomes and transcriptional data with functional testing of autologous peripheral blood mononuclear cells (PBMCs) to simultaneously identify and validate neoantigens recognized by naturally primed CD4+ and CD8+ T cell responses across a range of tumor types and mutational burdens. The method features a human leukocyte antigen (HLA)-agnostic bioinformatic algorithm that prioritizes mutations recognized by patient PBMCs at a greater than 40% positive predictive value followed by a short-term in vitro functional assay, which allows interrogation of 50 to 75 expressed mutations from a single 50-ml blood sample. Neoantigens validated by this method include both driver and passenger mutations, and this method identified neoantigens that would not have been otherwise detected using an in silico prediction approach. These findings reveal an efficient approach to systematically validate clinically actionable neoantigens and the T cell receptors that recognize them and demonstrate that patients across a variety of human cancers have a diverse repertoire of neoantigen-specific T cells.


Asunto(s)
Antígenos de Neoplasias , Neoplasias , Humanos , Antígenos de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/metabolismo , Linfocitos T CD8-positivos , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos Infiltrantes de Tumor
9.
Blood ; 118(5): 1294-304, 2011 Aug 04.
Artículo en Inglés | MEDLINE | ID: mdl-21562046

RESUMEN

We have discovered a distinct mature B-cell subset that accumulates with age, which we have termed age-associated B cells. These cells comprise up to 30% of mature B cells by 22 months. Despite sharing some features with other mature B-cell subsets, they are refractory to BCR and CD40 stimulation. Instead, they respond to TLR9 or TLR7 stimulation and divide maximally on combined BCR and TLR ligation, leading to Ig production and preferential secretion of IL-10 and IL-4. Although similar to follicular B cells in both B-lymphocyte stimulator (BLyS) receptor expression and BLyS binding capacity, these cells do not rely on BLyS for survival. They are neither cycling nor the result of intrinsically altered B lymphopoiesis in aged BM, but instead appear to be generated from mature B cells that exhaustively expand during the individual's lifetime. Finally, they present Ag effectively and favor polarization to a TH17 profile. Together, these findings reveal that while the magnitude of the mature primary B-cell niche is maintained with age, it is increasingly occupied by cells refractory to BCR-driven activation yet responsive to innate receptor stimulation.


Asunto(s)
Envejecimiento/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/fisiología , Proliferación Celular , Inmunidad Innata/fisiología , Activación de Linfocitos/fisiología , Animales , Factor Activador de Células B/metabolismo , Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/metabolismo , Células Cultivadas , Femenino , Inmunidad Innata/inmunología , Activación de Linfocitos/inmunología , Recuento de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Ratones Endogámicos DBA , Ratones Transgénicos
10.
JCI Insight ; 8(2)2023 Jan 24.
Artículo en Inglés | MEDLINE | ID: mdl-36512410

RESUMEN

CD4+ T cells play a critical role in antitumor immunity via recognition of peptide antigens presented on MHC class II (MHC-II). Although some solid cancers can be induced to express MHC-II, the extent to which this enables direct recognition by tumor-specific CD4+ T cells is unclear. We isolated and characterized T cell antigen receptors (TCRs) from naturally primed CD4+ T cells specific for 2 oncoproteins, HPV-16 E6 and the activating KRASG12V mutation, from patients with head and neck squamous cell carcinoma and pancreatic ductal adenocarcinoma, respectively, and determined their ability to recognize autologous or human leukocyte antigen-matched antigen-expressing tumor cells. We found in both cases that the TCRs were capable of recognizing peptide-loaded target cells expressing the relevant MHC-II or B cell antigen-presenting cells (APCs) when the antigens were endogenously expressed and directed to the endosomal pathway but failed to recognize tumor cells expressing the source protein even after induction of surface MHC-II expression by IFN-γ or transduction with CIITA. These results suggest that priming and functional recognition of both a nuclear (E6) and a membrane-associated (KRAS) oncoprotein are predominantly confined to crosspresenting APCs rather than via direct recognition of tumor cells induced to express MHC-II.


Asunto(s)
Linfocitos T CD4-Positivos , Neoplasias Pancreáticas , Humanos , Epítopos , Oncogenes , Antígenos HLA , Receptores de Antígenos de Linfocitos T/metabolismo , Neoplasias Pancreáticas/genética , Péptidos/metabolismo
11.
Mol Ther Oncolytics ; 27: 157-166, 2022 Dec 15.
Artículo en Inglés | MEDLINE | ID: mdl-36381658

RESUMEN

Innovative cell-based therapies are important new weapons in the fight against difficult-to-treat cancers. One promising strategy involves cell therapies equipped with multiple receptors to integrate signals from more than one antigen. We developed a specific embodiment of this approach called Tmod, a two-receptor system that combines activating and inhibitory inputs to distinguish between tumor and normal cells. The selectivity of Tmod is enforced by the inhibitory receptor (blocker) that recognizes an antigen, such as an HLA allele, whose expression is absent from tumors because of loss of heterozygosity. Although unwanted cross-reactivity of the blocker likely reduces efficacy rather than safety, it is important to verify the blocker's specificity. We have tested an A∗02-directed blocker derived from the PA2.1 mouse antibody as a safety mechanism paired with a mesothelin-specific activating CAR in our Tmod construct. We solved the crystal structure of humanized PA2.1 Fab in complex with HLA-A∗02 to determine its binding epitope, which was used to bioinformatically select specific class I HLA alleles to test the blocker's functional specificity in vitro. We found that this A∗02-directed blocker is highly specific for its cognate antigen, with only one cross-reactive allele (A∗69) capable of triggering comparable function.

12.
Cancer Res Commun ; 2(1): 58-65, 2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-36860694

RESUMEN

Neoantigens are among the most intriguing potential immuno-oncology targets because, unlike many cancer targets that are expressed on normal tissues, they are by definition restricted to cancer cells. Medicines directed at common neoantigens such as mutant KRAS are especially interesting because they may offer the convenience and cost of an off-the-shelf therapy. However, all common KRAS mutations produce proteins that differ from the wild type at a single amino acid, creating challenges for molecular discrimination. We have undertaken an effort to optimize single-chain variable fragments (scFv) against peptide/major histocompatibility antigen complexes composed of HLA-A*11 and either G12V- or G12D-mutant KRAS peptides. These scFvs could in principle be used in chimeric antigen receptor (CAR) T-cell therapies for selected patients whose tumors bear either of these mutations. Here we show that optimization of such CARs involves a trade-off between potency and selectivity. We further show that targeting this family without high selectivity engenders risks of cross-reactivity against other members of the G-protein family to which KRAS belongs. Significance: We report an effort to generate high potency, selective CARs directed at mutant KRAS peptides. Although the heavily optimized CARs maintain high selectivity against wild-type KRAS, they lose selectivity against other KRAS-related peptides derived from human proteins. To our knowledge, this work is the first to examine the trade-off between potency and selectivity with regard to KRAS pMHC-directed CARs, illustrating the challenge to achieve both sufficient potency and high selectivity.


Asunto(s)
Neoplasias , Receptores Quiméricos de Antígenos , Anticuerpos de Cadena Única , Humanos , Receptores Quiméricos de Antígenos/genética , Proteínas Proto-Oncogénicas p21(ras)/genética , Inmunoterapia Adoptiva , Anticuerpos de Cadena Única/genética
13.
J Immunother Cancer ; 10(1)2022 01.
Artículo en Inglés | MEDLINE | ID: mdl-35091455

RESUMEN

BACKGROUND: Mesothelin (MSLN) is a classic tumor-associated antigen that is expressed in lung cancer and many other solid tumors. However, MSLN is also expressed in normal mesothelium which creates a significant risk of serious inflammation for MSLN-directed therapeutics. We have developed a dual-receptor (Tmod™) system that exploits the difference between tumor and normal tissue in a subset of patients with defined heterozygous gene loss (LOH) in their tumors. METHODS: T cells engineered with the MSLN CAR Tmod construct described here contain (1) a novel MSLN-activated CAR and (2) an HLA-A*02-gated inhibitory receptor (blocker). A*02 binding is intended to override T-cell cytotoxicity, even in the presence of MSLN. The Tmod system is designed to treat heterozygous HLA class I patients, selected for HLA LOH. When A*02 is absent from tumors selected for LOH, the MSLN Tmod cells are predicted to mediate potent killing of the MSLN(+)A*02(-) malignant cells. RESULTS: The sensitivity of the MSLN Tmod cells is comparable with a benchmark MSLN CAR-T that was active but toxic in the clinic. Unlike MSLN CAR-T cells, the Tmod system robustly protects surrogate "normal" cells even in mixed-cell populations in vitro and in a xenograft model. The MSLN CAR can also be paired with other HLA class I blockers, supporting extension of the approach to patients beyond A*02 heterozygotes. CONCLUSIONS: The Tmod mechanism exemplified by the MSLN CAR Tmod construct provides an alternative route to leverage solid-tumor antigens such as MSLN in safer, more effective ways than previously possible.


Asunto(s)
Antígeno HLA-A2/genética , Inmunoterapia Adoptiva/métodos , Mesotelina/inmunología , Neoplasias/terapia , Receptores Quiméricos de Antígenos/inmunología , Animales , Línea Celular Tumoral , Femenino , Antígeno HLA-A2/inmunología , Humanos , Pérdida de Heterocigocidad , Ratones , Linfocitos T/inmunología , Ensayos Antitumor por Modelo de Xenoinjerto
14.
J Leukoc Biol ; 107(4): 625-633, 2020 04.
Artículo en Inglés | MEDLINE | ID: mdl-32170883

RESUMEN

The goal of precision immunotherapy is to direct a patient's T cell response against the immunogenic mutations expressed on their tumors. Most immunotherapy approaches to-date have focused on MHC class I-restricted peptide epitopes by which cytotoxic CD8+ T lymphocytes (CTL) can directly recognize tumor cells. This strategy largely overlooks the critical role of MHC class II-restricted CD4+ T cells as both positive regulators of CTL and other effector cell types, and as direct effectors of antitumor immunity. In this review, we will discuss the role of neoantigen specific CD4+ T cells in cancer immunotherapy and how existing treatment modalities may be leveraged to engage this important T cell subset.


Asunto(s)
Antígenos de Neoplasias/metabolismo , Inmunoterapia , Neoplasias/inmunología , Neoplasias/terapia , Animales , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/inmunología , Humanos , Linfocitos T Colaboradores-Inductores/inmunología
15.
J Exp Med ; 215(6): 1571-1588, 2018 06 04.
Artículo en Inglés | MEDLINE | ID: mdl-29739835

RESUMEN

T follicular helper (Tfh) cells are required to develop germinal center (GC) responses and drive immunoglobulin class switch, affinity maturation, and long-term B cell memory. In this study, we characterize a recently developed vaccine platform, nucleoside-modified, purified mRNA encapsulated in lipid nanoparticles (mRNA-LNPs), that induces high levels of Tfh and GC B cells. Intradermal vaccination with nucleoside-modified mRNA-LNPs encoding various viral surface antigens elicited polyfunctional, antigen-specific, CD4+ T cell responses and potent neutralizing antibody responses in mice and nonhuman primates. Importantly, the strong antigen-specific Tfh cell response and high numbers of GC B cells and plasma cells were associated with long-lived and high-affinity neutralizing antibodies and durable protection. Comparative studies demonstrated that nucleoside-modified mRNA-LNP vaccines outperformed adjuvanted protein and inactivated virus vaccines and pathogen infection. The incorporation of noninflammatory, modified nucleosides in the mRNA is required for the production of large amounts of antigen and for robust immune responses.


Asunto(s)
Linfocitos B/inmunología , Centro Germinal/citología , Nucleósidos/metabolismo , ARN Mensajero/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Vacunas de Subunidad/inmunología , Adyuvantes Inmunológicos/farmacología , Animales , Anticuerpos Neutralizantes/inmunología , Formación de Anticuerpos/inmunología , Antígenos/metabolismo , Lípidos/química , Macaca mulatta , Nanopartículas/química , Subunidades de Proteína/metabolismo , Factores de Tiempo , Vacunación
16.
Curr Opin Immunol ; 34: 126-9, 2015 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-25836418

RESUMEN

The BAFF family of receptors and ligands controls B cell homeostasis and selection. Recent studies reveal distinct sources and roles for systemic versus locally produced BAFF. Moreover, the notion that differential BAFF receptor expression patterns establish independent homeostatic and selective niches has been strengthened. Finally, unique roles for BAFF family members in the regulation of antigen experienced and innate B cell subsets have been revealed. Herein, we overview current knowledge in these areas, emphasizing recent findings that inform these ideas.


Asunto(s)
Subgrupos de Linfocitos B/citología , Subgrupos de Linfocitos B/inmunología , Animales , Receptor del Factor Activador de Células B/metabolismo , Microambiente Celular , Homeostasis , Humanos , Memoria Inmunológica , Miembro 13 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/metabolismo
17.
Exp Gerontol ; 54: 109-15, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24389058

RESUMEN

We examined whether age alters the emergence of high-affinity germinal center B (GCB) cells and switched memory B cells (swBmem) during a primary immune response to a thymus-dependent antigen, using a novel flow cytometric assay to distinguish relative BCR affinity. In young mice, high-affinity B cells predominate in the GCB pool and comprise a smaller proportion of the nascent swBmem pool two weeks after immunization. In aged mice, we observe significant reductions of high-affinity clones among GCB cells, but not nascent swBmem cells. The defect in GC affinity maturation was not overcome by providing excess carrier-specific T cells from young mice, as these cells still displayed compromised effector TFH differentiation in the aged animals. Our results suggest that B cells in aged animals have a reduced ability to prompt effector TFH differentiation, leading to a compromised GC response that results in reduced generation of high-affinity GCB and plasma cells; despite normal production of early swBmem cells.


Asunto(s)
Envejecimiento/inmunología , Linfocitos B/inmunología , Centro Germinal/inmunología , Memoria Inmunológica/fisiología , Animales , Linfocitos T CD4-Positivos/trasplante , Diferenciación Celular/inmunología , Ratones Endogámicos C57BL , Linfocitos T Colaboradores-Inductores/inmunología
SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA