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1.
Immunity ; 54(12): 2877-2892.e7, 2021 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-34852217

RESUMEN

Adjuvants are critical for improving the quality and magnitude of adaptive immune responses to vaccination. Lipid nanoparticle (LNP)-encapsulated nucleoside-modified mRNA vaccines have shown great efficacy against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), but the mechanism of action of this vaccine platform is not well-characterized. Using influenza virus and SARS-CoV-2 mRNA and protein subunit vaccines, we demonstrated that our LNP formulation has intrinsic adjuvant activity that promotes induction of strong T follicular helper cell, germinal center B cell, long-lived plasma cell, and memory B cell responses that are associated with durable and protective antibodies in mice. Comparative experiments demonstrated that this LNP formulation outperformed a widely used MF59-like adjuvant, AddaVax. The adjuvant activity of the LNP relies on the ionizable lipid component and on IL-6 cytokine induction but not on MyD88- or MAVS-dependent sensing of LNPs. Our study identified LNPs as a versatile adjuvant that enhances the efficacy of traditional and next-generation vaccine platforms.


Asunto(s)
Linfocitos B/inmunología , Vacunas contra la COVID-19/inmunología , COVID-19/inmunología , Centro Germinal/inmunología , SARS-CoV-2/fisiología , Linfocitos T Colaboradores-Inductores/inmunología , Vacunas de ARNm/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Adyuvantes Inmunológicos , Animales , Células HEK293 , Humanos , Inmunidad Humoral , Interleucina-6/genética , Interleucina-6/metabolismo , Liposomas/administración & dosificación , Ratones , Ratones Endogámicos BALB C , Nanopartículas/administración & dosificación , Subunidades de Proteína/genética , Vacunas de ARNm/genética
2.
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 Cell Biol ; 102(4): 229-231, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38525813

RESUMEN

Age-associated B cells (ABCs) are a stable subset of memory B lymphocytes that develop during microbial infections and in autoimmune diseases. Despite growing appreciation of their phenotypic and functional characteristics, the transcriptional networks involved in ABC fate commitment and maintenance have remained elusive. In their recent publication, Dai et al. tackle this problem, leveraging both mouse models and human diseases to reveal zinc finger E-box-binding homeobox 2 (ZEB2) as a key transcriptional regulator of ABC lineage specification. In aggregate, their results show that ZEB2, a member of the zinc finger E homeobox binding family, promotes ABC differentiation by repressing alternative differentiative fates and targeting genes important for ABC character and function. Moreover, their results strengthen the case for causal links between ABC fate and function in autoimmune pathologies.


Asunto(s)
Proteínas de Unión al ADN , Factores de Transcripción , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc , Animales , Humanos , Ratones , Diferenciación Celular , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/genética , Caja Homeótica 2 de Unión a E-Box con Dedos de Zinc/metabolismo
5.
Proc Natl Acad Sci U S A ; 118(24)2021 06 15.
Artículo en Inglés | MEDLINE | ID: mdl-34103397

RESUMEN

Systemic lupus erythematous (SLE) is a female-predominant disease characterized by autoimmune B cells and pathogenic autoantibody production. Individuals with two or more X chromosomes are at increased risk for SLE, suggesting that X-linked genes contribute to the observed sex bias of this disease. To normalize X-linked gene expression between sexes, one X in female cells is randomly selected for transcriptional silencing through X-chromosome inactivation (XCI), resulting in allele-specific enrichment of epigenetic modifications, including histone methylation and the long noncoding RNA XIST/Xist on the inactive X (Xi). As we have previously shown that epigenetic regulation of the Xi in female lymphocytes from mice is unexpectedly dynamic, we used RNA fluorescence in situ hybridization and immunofluorescence to profile epigenetic features of the Xi at the single-cell level in human B cell subsets from pediatric and adult SLE patients and healthy controls. Our data reveal that abnormal XCI maintenance in B cells is a feature of SLE. Using single-cell and bulk-cell RNA sequencing datasets, we found that X-linked immunity genes escape XCI in specific healthy human B cell subsets and that human SLE B cells exhibit aberrant expression of X-linked genes and XIST RNA interactome genes. Our data reveal that mislocalized XIST RNA, coupled with a dramatic reduction in heterochromatic modifications at the Xi in SLE, predispose for aberrant X-linked gene expression from the Xi, thus defining a genetic and epigenetic pathway that affects X-linked gene expression in human SLE B cells and likely contributes to the female bias in SLE.


Asunto(s)
Linfocitos B/metabolismo , Cromosomas Humanos X/genética , Epigénesis Genética , Lupus Eritematoso Sistémico/genética , Inactivación del Cromosoma X/genética , Adolescente , Adulto , Alelos , Niño , Perfilación de la Expresión Génica , Heterocromatina/metabolismo , Histonas/metabolismo , Humanos , Subgrupos Linfocitarios/metabolismo , Lisina/metabolismo , Metilación , Persona de Mediana Edad , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Ubiquitina/metabolismo , Adulto Joven
6.
Immunol Rev ; 288(1): 149-160, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30874358

RESUMEN

B cells expressing the transcription factor T-bet have emerged as participants in a number of protective and pathogenic immune responses. T-bet+ B cells characteristically differentiate in response to combined Toll-like receptor and cytokine signaling, contribute to protective immunity against intracellular pathogens via IgG2a/c production and antibody-independent mechanisms, and are prone to produce autoantibodies. Despite recent advances, a number of questions remain regarding the basic biology of T-bet+ B cells and their functional niche within the immune system. Herein, we review the discovery and defining characteristics of the T-bet+ B cell subset in both mice and humans. We further discuss their origins, the basis for their persistence, and their potential fate in vivo. Evidence indicates that T-bet+ B cells represent a distinct, germinal center-derived memory population that may serve as an important therapeutic target for the improvement of humoral immunity and prevention of autoimmunity.


Asunto(s)
Autoanticuerpos/metabolismo , Subgrupos de Linfocitos B/inmunología , Linfocitos B/inmunología , Proteínas de Dominio T Box/metabolismo , Animales , Autoinmunidad , Diferenciación Celular , Citocinas/metabolismo , Humanos , Memoria Inmunológica , Activación de Linfocitos , Ratones , Transducción de Señal , Proteínas de Dominio T Box/genética , Receptores Toll-Like/metabolismo
7.
Infect Immun ; 87(12)2019 12.
Artículo en Inglés | MEDLINE | ID: mdl-31548322

RESUMEN

Interleukin-27 (IL-27) is a heterodimeric cytokine composed of the subunits IL-27p28 and EBi3, and while the IL-27 heterodimer influences T cell activities, there is evidence that IL-27p28 can have EBi3-independent activities; however, their relevance to infection is unclear. Therefore, the studies presented here compared how IL-27p28 transgenics and IL-27p28-/- mice responded to the intracellular parasite Toxoplasma gondii While the loss of IL-27p28 and its overexpression both result in increased susceptibility to T. gondii, the basis for this phenotype reveals distinct roles for IL-27p28. As a component of IL-27, IL-27p28 is critical to limit infection-induced T cell-mediated pathology, whereas the ectopic expression of IL-27p28 reduced the effector T cell population and had a major inhibitory effect on parasite-specific antibody titers and a failure to control parasite replication in the central nervous system. Indeed, transfer of immune serum to infected IL-27p28 transgenics resulted in reduced parasite burden and pathology. Thus, IL-27p28, independent of its role as a component of IL-27, can act as a negative regulator of humoral and cellular responses during toxoplasmosis.


Asunto(s)
Linfocitos B/inmunología , Interleucinas/genética , Linfocitos T/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Animales , Anticuerpos Antiprotozoarios/sangre , Anticuerpos Antiprotozoarios/inmunología , Sistema Nervioso Central/parasitología , Femenino , Interleucinas/inmunología , Masculino , Ratones , Ratones Endogámicos C57BL , Toxoplasmosis/parasitología
8.
Cell Immunol ; 321: 26-34, 2017 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-28739077

RESUMEN

T-bet-expressing B cells, first identified as perpetuators of autoimmunity, were recently shown to be critical for murine antiviral responses. While their role in human viral infections remains unclear, B cells expressing T-bet or demonstrating a related phenotype have been described in individuals chronically infected with HIV or HCV, suggesting these cells represent a component of human antiviral responses. In this review, we discuss the induction of T-bet in B cells following both HIV and HCV infections, the factors driving T-bet+ B cell expansions, T-bet's relationship to atypical memory B cells, and the consequences of T-bet induction. We propose potential antiviral roles for T-bet+ B cells and discuss whether this population poses any utility to the HIV and HCV immune responses.


Asunto(s)
Linfocitos B/inmunología , Infecciones por VIH/inmunología , Hepatitis C/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Anticuerpos Antivirales/inmunología , Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Linfocitos B/metabolismo , Humanos , Inmunoglobulina G/inmunología , Modelos Inmunológicos , Proteínas de Dominio T Box/metabolismo
9.
bioRxiv ; 2024 Sep 16.
Artículo en Inglés | MEDLINE | ID: mdl-39345402

RESUMEN

Autoimmune destruction of pancreatic ß cells results in type 1 diabetes (T1D), with pancreatic immune infiltrate representing a key feature in this process. Studies of human T1D immunobiology have predominantly focused on circulating immune cells in the blood, while mouse models suggest diabetogenic lymphocytes primarily reside in pancreas-draining lymph nodes (pLN). A comprehensive study of immune cells in human T1D was conducted using pancreas draining lymphatic tissues, including pLN and mesenteric lymph nodes, and the spleen from non-diabetic control, ß cell autoantibody positive non-diabetic (AAb+), and T1D organ donors using complementary approaches of high parameter flow cytometry and CITEseq. Immune perturbations suggestive of a proinflammatory environment were specific for T1D pLN and AAb+ pLN. In addition, certain immune populations correlated with high T1D genetic risk independent of disease state. These datasets form an extensive resource for profiling human lymphatic tissue immune cells in the context of autoimmunity and T1D.

10.
Nat Nanotechnol ; 18(9): 1105-1114, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37365276

RESUMEN

Lipid nanoparticle (LNP)-formulated messenger RNA (mRNA) vaccineare a promising platform to prevent infectious diseases as demonstrated by the recent success of SARS-CoV-2 mRNA vaccines. To avoid immune recognition and uncontrolled inflammation, nucleoside-modified mRNA is used. However, such modification largely abrogates the innate immune responses that are critical to orchestrating robust adaptive immunity. Here we develop an LNP component-an adjuvant lipidoid-that can enhance the adjuvanticity of mRNA-LNP vaccines. Our results show that partial substitution of ionizable lipidoid with adjuvant lipidoid not only enhanced mRNA delivery, but also endowed LNPs with Toll-like receptor 7/8-agonistic activity, which significantly increased the innate immunity of the SARS-CoV-2 mRNA-LNP vaccine with good tolerability in mice. Our optimized vaccine elicits potent neutralizing antibodies against multiple SARS-CoV-2 pseudovirus variants, strong Th1-biased cellular immunity, and robust B cell and long-lived plasma cell responses. Importantly, this adjuvant lipidoid substitution strategy works successfully in a clinically relevant mRNA-LNP vaccine, demonstrating its translational potential.


Asunto(s)
COVID-19 , Nanopartículas , Animales , Humanos , Ratones , Vacunas contra la COVID-19 , SARS-CoV-2/genética , COVID-19/prevención & control , Adyuvantes Inmunológicos/farmacología , ARN Mensajero/genética , Vacunas de ARNm
11.
Cell Rep Med ; 4(12): 101336, 2023 12 19.
Artículo en Inglés | MEDLINE | ID: mdl-38118406

RESUMEN

Pre-existing anti-human leukocyte antigen (HLA) allo-antibodies constitute a major barrier to transplantation. Current desensitization approaches fail due to ineffective depletion of allo-specific memory B cells (Bmems) and long-lived plasma cells (LLPCs). We evaluate the efficacy of chimeric antigen receptor (CAR) T cells targeting CD19 and B cell maturation antigen (BCMA) to eliminate allo-antibodies in a skin pre-sensitized murine model of islet allo-transplantation. We find that treatment of allo-sensitized hosts with CAR T cells targeting Bmems and LLPCs eliminates donor-specific allo-antibodies (DSAs) and mitigates hyperacute rejection of subsequent islet allografts. We then assess the clinical efficacy of the CAR T therapy for desensitization in patients with multiple myeloma (MM) with pre-existing HLA allo-antibodies who were treated with the combination of CART-BCMA and CART-19 (ClinicalTrials.gov: NCT03549442) and observe clinically meaningful allo-antibody reduction. These findings provide logical rationale for clinical evaluation of CAR T-based immunotherapy in highly sensitized candidates to promote successful transplantation.


Asunto(s)
Receptores Quiméricos de Antígenos , Humanos , Animales , Ratones , Células Plasmáticas , Antígeno de Maduración de Linfocitos B , Linfocitos T , Inmunoterapia , Anticuerpos
12.
J Clin Invest ; 131(23)2021 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-34618692

RESUMEN

Nucleoside-modified mRNA vaccines have gained global attention because of COVID-19. We evaluated a similar vaccine approach for preventing a chronic, latent genital infection rather than an acute respiratory infection. We used animal models to compare an HSV-2 trivalent nucleoside-modified mRNA vaccine with the same antigens prepared as proteins, with an emphasis on antigen-specific memory B cell responses and immune correlates of protection. In guinea pigs, serum neutralizing-antibody titers were higher at 1 month and declined far less by 8 months in mRNA- compared with protein-immunized animals. Both vaccines protected against death and genital lesions when infected 1 month after immunization; however, protection was more durable in the mRNA group compared with the protein group when infected after 8 months, an interval representing greater than 15% of the animal's lifespan. Serum and vaginal neutralizing-antibody titers correlated with protection against infection, as measured by genital lesions and vaginal virus titers 2 days after infection. In mice, the mRNA vaccine generated more antigen-specific memory B cells than the protein vaccine at early times after immunization that persisted for up to 1 year. High neutralizing titers and robust B cell immune memory likely explain the more durable protection by the HSV-2 mRNA vaccine.


Asunto(s)
Herpes Genital , Herpesvirus Humano 2/inmunología , Memoria Inmunológica , Células B de Memoria/inmunología , ARN Viral/inmunología , Vacunas Sintéticas/inmunología , Vacunas Virales/inmunología , Animales , COVID-19/inmunología , COVID-19/prevención & control , Modelos Animales de Enfermedad , Femenino , Cobayas , Herpes Genital/inmunología , Herpes Genital/prevención & control , SARS-CoV-2/inmunología , Vacunas de ARNm
13.
Cell Host Microbe ; 29(9): 1437-1453.e8, 2021 09 08.
Artículo en Inglés | MEDLINE | ID: mdl-34428428

RESUMEN

The SARS-CoV-2 pandemic has affected more than 185 million people worldwide resulting in over 4 million deaths. To contain the pandemic, there is a continued need for safe vaccines that provide durable protection at low and scalable doses and can be deployed easily. Here, AAVCOVID-1, an adeno-associated viral (AAV), spike-gene-based vaccine candidate demonstrates potent immunogenicity in mouse and non-human primates following a single injection and confers complete protection from SARS-CoV-2 challenge in macaques. Peak neutralizing antibody titers are sustained at 1 year and complemented by functional memory T cell responses. The AAVCOVID vector has no relevant pre-existing immunity in humans and does not elicit cross-reactivity to common AAVs used in gene therapy. Vector genome persistence and expression wanes following injection. The single low-dose requirement, high-yield manufacturability, and 1-month stability for storage at room temperature may make this technology well suited to support effective immunization campaigns for emerging pathogens on a global scale.


Asunto(s)
Anticuerpos Neutralizantes/sangre , Anticuerpos Antivirales/sangre , Vacunas contra la COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Vacunas contra la COVID-19/administración & dosificación , Vacunas contra la COVID-19/genética , Dependovirus/genética , Dependovirus/metabolismo , Femenino , Humanos , Inmunogenicidad Vacunal/inmunología , Memoria Inmunológica/inmunología , Macaca fascicularis , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Linfocitos T/inmunología , Transgenes/genética , Vacunación/métodos , Carga Viral/inmunología
14.
bioRxiv ; 2021 Jan 19.
Artículo en Inglés | MEDLINE | ID: mdl-33442684

RESUMEN

The SARS-CoV-2 pandemic has affected more than 70 million people worldwide and resulted in over 1.5 million deaths. A broad deployment of effective immunization campaigns to achieve population immunity at global scale will depend on the biological and logistical attributes of the vaccine. Here, two adeno-associated viral (AAV)-based vaccine candidates demonstrate potent immunogenicity in mouse and nonhuman primates following a single injection. Peak neutralizing antibody titers remain sustained at 5 months and are complemented by functional memory T-cells responses. The AAVrh32.33 capsid of the AAVCOVID vaccine is an engineered AAV to which no relevant pre-existing immunity exists in humans. Moreover, the vaccine is stable at room temperature for at least one month and is produced at high yields using established commercial manufacturing processes in the gene therapy industry. Thus, this methodology holds as a very promising single dose, thermostable vaccine platform well-suited to address emerging pathogens on a global scale.

15.
JCI Insight ; 2(8)2017 Apr 20.
Artículo en Inglés | MEDLINE | ID: mdl-28422752

RESUMEN

Humoral immunity is critical for viral control, but the identity and mechanisms regulating human antiviral B cells are unclear. Here, we characterized human B cells expressing T-bet and analyzed their dynamics during viral infections. T-bet+ B cells demonstrated an activated phenotype, a distinct transcriptional profile, and were enriched for expression of the antiviral immunoglobulin isotypes IgG1 and IgG3. T-bet+ B cells expanded following yellow fever virus and vaccinia virus vaccinations and also during early acute HIV infection. Viremic HIV-infected individuals maintained a large T-bet+ B cell population during chronic infection that was associated with increased serum and cell-associated IgG1 and IgG3 expression. The HIV gp140-specific B cell response was dominated by T-bet-expressing memory B cells, and we observed a concomitant biasing of gp140-specific serum immunoglobulin to the IgG1 isotype. These findings suggest that T-bet induction promotes antiviral immunoglobulin isotype switching and development of a distinct T-bet+ B cell subset that is maintained by viremia and coordinates the HIV Env-specific humoral response.

16.
Front Immunol ; 7: 337, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27610109

RESUMEN

[This corrects the article on p. 217 in vol. 5, PMID: 24860576.].

17.
Front Immunol ; 5: 217, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24860576

RESUMEN

The T-box transcription factors T-bet and Eomesodermin (Eomes) have been well defined as key drivers of immune cell development and cytolytic function. While the majority of studies have defined the roles of these factors in the context of murine T-cells, recent results have revealed that T-bet, and possibly Eomes, are expressed in other immune cell subsets. To date, the expression patterns of these factors in subsets of human peripheral blood mononuclear cells beyond T-cells remain relatively uncharacterized. In this study, we used multiparametric flow cytometry to characterize T-bet and Eomes expression in major human blood cell subsets, including total CD4(+) and CD8(+) T-cells, γδ T-cells, invariant NKT cells, natural killer cells, B-cells, and dendritic cells. Our studies identified novel cell subsets that express T-bet and Eomes and raise implications for their possible functions in the context of other human immune cell subsets besides their well-known roles in T-cells.

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