RESUMEN
Tools to study memory B cell (MBC) development and function are needed to understand their role in supporting sustained protection against recurrent infections. While human MBCs are traditionally measured using blood, there is a growing interest in elucidating their behavior within lymphoid tissues, which are the main sites where adaptive immune responses are orchestrated. In this chapter, we introduce a high-throughput organoid system that is derived from primary human lymphoid tissues. The approach can recapitulate many hallmarks of successful adaptive immune responses and capture inter-individual variation in response to a variety of stimuli. Lymphoid tissue organoids enable characterization of pre-existing antigen-specific MBCs within an entirely human system and can provide valuable insights into MBC dynamics.
Asunto(s)
Linfocitos B , Memoria Inmunológica , Organoides , Tonsila Palatina , Humanos , Organoides/citología , Organoides/inmunología , Tonsila Palatina/citología , Tonsila Palatina/inmunología , Linfocitos B/inmunología , Linfocitos B/citología , Técnicas de Cultivo de Célula/métodos , Células CultivadasRESUMEN
Sex-based differences in immune cell composition and function can contribute to distinct adaptive immune responses. Prior work has quantified these differences in peripheral blood, but little is known about sex differences within human lymphoid tissues. Here, we characterized the composition and phenotypes of adaptive immune cells from male and female ex vivo tonsils and evaluated their responses to influenza antigens using an immune organoid approach. In a pediatric cohort, female tonsils had more memory B cells compared to male tonsils direct ex vivo and after stimulation with live-attenuated but not inactivated vaccine, produced higher influenza-specific antibody responses. Sex biases were also observed in adult tonsils but were different from those measured in children. Analysis of peripheral blood immune cells from in vivo vaccinated adults also showed higher frequencies of tissue homing CD4 T cells in female participants. Together, our data demonstrate that distinct memory B and T cell profiles are present in male vs. female lymphoid tissues and peripheral blood respectively and suggest that these differences may in part explain sex biases in response to vaccines and viruses.
Asunto(s)
Tonsila Palatina , Humanos , Femenino , Masculino , Niño , Tonsila Palatina/inmunología , Adulto , Vacunas contra la Influenza/inmunología , Gripe Humana/inmunología , Caracteres Sexuales , Preescolar , Adolescente , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Células B de Memoria/inmunología , Especificidad de Órganos/inmunología , Adulto Joven , Factores Sexuales , Linfocitos T CD4-Positivos/inmunología , Linfocitos B/inmunología , Memoria InmunológicaRESUMEN
Heterogeneity in the tumor microenvironment (TME) of follicular lymphomas (FLs) can affect clinical outcomes. Current immunotherapeutic strategies, including antibody- and cell-based therapies, variably overcome pro-tumorigenic mechanisms for sustained disease control. Modeling the intact FL TME, with its native, syngeneic tumor-infiltrating leukocytes, is a major challenge. Here, we describe an organoid culture method for cultivating patient-derived lymphoma organoids (PDLOs), which include cells from the native FL TME. We define the robustness of this method by successfully culturing cryopreserved FL specimens from diverse patients and demonstrate the stability of TME cellular composition, tumor somatic mutations, gene expression profiles, and B/T cell receptor dynamics over 3 weeks. PDLOs treated with CD3:CD19 and CD3:CD20 therapeutic bispecific antibodies showed B cell killing and T cell activation. This stable system offers a robust platform for advancing precision medicine efforts in FL through patient-specific modeling, high-throughput screening, TME signature identification, and treatment response evaluation.
Asunto(s)
Linfoma Folicular , Humanos , Linfoma Folicular/terapia , Linfoma Folicular/diagnóstico , Linfoma Folicular/genética , Microambiente Tumoral , Linfocitos B , Receptores de Antígenos de Linfocitos T , OrganoidesRESUMEN
Current influenza A and B virus (IABV) vaccines provide suboptimal protection and efforts are underway to develop a universal IABV vaccine. Blood neutralizing antibodies are the current gold standard for protection, but many processes that regulate human IABV-specific immunity occur in mucosal and lymphoid tissues. We need an improved mechanistic understanding of how immune cells respond within these tissues to advance our current (slow and expensive) vaccine testing model. We posit that advanced in vitro models of human adaptive immunity can bridge some of the gaps between vaccine design, animal models, and human clinical trials. Here, we highlight how they can be integrated into current practices and play a role in reverse translating the defined features of protective vaccines to rationally design new candidates.
Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Animales , Humanos , Anticuerpos Antivirales , Anticuerpos Neutralizantes , Inmunidad Adaptativa , Organoides , Gripe Humana/prevención & controlRESUMEN
Highly effective vaccines elicit specific, robust, and durable adaptive immune responses. To advance informed vaccine design, it is critical that we understand the cellular dynamics underlying responses to different antigen formats. Here, we sought to understand how antigen-specific B and T cells were activated and participated in adaptive immune responses within the mucosal site. Using a human tonsil organoid model, we tracked the differentiation and kinetics of the adaptive immune response to influenza vaccine and virus modalities. Each antigen format elicited distinct B and T cell responses, including differences in their magnitude, diversity, phenotype, function, and breadth. These differences culminated in substantial changes in the corresponding antibody response. A major source of antigen format-related variability was the ability to recruit naive vs. memory B and T cells to the response. These findings have important implications for vaccine design and the generation of protective immune responses in the upper respiratory tract.
Asunto(s)
Vacunas contra la Influenza , Gripe Humana , Humanos , Formación de Anticuerpos , Anticuerpos Antivirales , Linfocitos T , Antígenos , OrganoidesRESUMEN
The ideal vaccine against viruses such as influenza and SARS-CoV-2 must provide a robust, durable and broad immune protection against multiple viral variants. However, antibody responses to current vaccines often lack robust cross-reactivity. Here we describe a polymeric Toll-like receptor 7 agonist nanoparticle (TLR7-NP) adjuvant, which enhances lymph node targeting, and leads to persistent activation of immune cells and broad immune responses. When mixed with alum-adsorbed antigens, this TLR7-NP adjuvant elicits cross-reactive antibodies for both dominant and subdominant epitopes and antigen-specific CD8+ T-cell responses in mice. This TLR7-NP-adjuvanted influenza subunit vaccine successfully protects mice against viral challenge of a different strain. This strategy also enhances the antibody response to a SARS-CoV-2 subunit vaccine against multiple viral variants that have emerged. Moreover, this TLR7-NP augments antigen-specific responses in human tonsil organoids. Overall, we describe a nanoparticle adjuvant to improve immune responses to viral antigens, with promising implications for developing broadly protective vaccines.
Asunto(s)
COVID-19 , Vacunas contra la Influenza , Gripe Humana , Nanopartículas , Animales , Ratones , Humanos , Gripe Humana/prevención & control , Receptor Toll-Like 7/genética , SARS-CoV-2/genética , COVID-19/prevención & control , Adyuvantes Inmunológicos/farmacología , Inmunidad , Vacunas de SubunidadRESUMEN
The germinal center (GC) response is critical for both effective adaptive immunity and establishing peripheral tolerance by limiting autoreactive B cells. Dysfunction in these processes can lead to defective immune responses to infection or contribute to autoimmune disease. To understand the gene regulatory principles underlying the GC response, we generated a single-cell transcriptomic and epigenomic atlas of the human tonsil, a widely studied and representative lymphoid tissue. We characterize diverse immune cell subsets and build a trajectory of dynamic gene expression and transcription factor activity during B cell activation, GC formation, and plasma cell differentiation. We subsequently leverage cell typespecific transcriptomic and epigenomic maps to interpret potential regulatory impact of genetic variants implicated in autoimmunity, revealing that many exhibit their greatest regulatory potential in GC-associated cellular populations. These included gene loci linked with known roles in GC biology (IL21, IL21R, IL4R, and BCL6) and transcription factors regulating B cell differentiation (POU2AF1 and HHEX). Together, these analyses provide a powerful new cell typeresolved resource for the interpretation of cellular and genetic causes underpinning autoimmune disease.
Asunto(s)
Autoinmunidad/inmunología , Centro Germinal/inmunología , Proteínas de Homeodominio/inmunología , Interleucinas/inmunología , Análisis de la Célula Individual , Transactivadores/inmunología , Factores de Transcripción/inmunología , Diferenciación Celular/inmunología , Epigenómica , Proteínas de Homeodominio/genética , Humanos , Interleucinas/genética , Tonsila Palatina/inmunología , Análisis de Secuencia de ARN , Transactivadores/genética , Factores de Transcripción/genética , TranscriptomaRESUMEN
Most of what we know about adaptive immunity has come from inbred mouse studies, using methods that are often difficult or impossible to confirm in humans. In addition, vaccine responses in mice are often poorly predictive of responses to those same vaccines in humans. Here we use human tonsils, readily available lymphoid organs, to develop a functional organotypic system that recapitulates key germinal center features in vitro, including the production of antigen-specific antibodies, somatic hypermutation and affinity maturation, plasmablast differentiation and class-switch recombination. We use this system to define the essential cellular components necessary to produce an influenza vaccine response. We also show that it can be used to evaluate humoral immune responses to two priming antigens, rabies vaccine and an adenovirus-based severe acute respiratory syndrome coronavirus 2 vaccine, and to assess the effects of different adjuvants. This system should prove useful for studying critical mechanisms underlying adaptive immunity in much greater depth than previously possible and to rapidly test vaccine candidates and adjuvants in an entirely human system.
Asunto(s)
Vacunas contra la Influenza/inmunología , Tonsila Palatina/inmunología , Adyuvantes Inmunológicos , Linfocitos B/citología , Linfocitos B/inmunología , Vacunas contra la COVID-19/inmunología , Centro Germinal/citología , Glicoproteínas Hemaglutininas del Virus de la Influenza , Humanos , Técnicas In Vitro , Tejido Linfoide/inmunología , Vacuna contra el Sarampión-Parotiditis-Rubéola/inmunología , Organoides/citología , Organoides/inmunología , Vacunas Antirrábicas/inmunología , Linfocitos T/inmunologíaRESUMEN
Antibodies are typically thought to mediate antiviral immunity by blocking host-cell infection. However, immunoglobulin G (IgG) can also stimulate antiviral responses through its constant region. A recent study in Nature (Bournazos et al., 2020) shows that modifying Fc binding affinities to better target FcɣRIIa enhances the influenza CD8 T cell response.
Asunto(s)
Gripe Humana , Orthomyxoviridae , Anticuerpos Antivirales , Linfocitos T CD8-positivos , Humanos , Fragmentos Fc de InmunoglobulinasRESUMEN
The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange. Three-dimensional in vitro human distal lung culture systems would strongly facilitate the investigation of pathologies such as interstitial lung disease, cancer and coronavirus disease 2019 (COVID-19) pneumonia caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here we describe the development of a long-term feeder-free, chemically defined culture system for distal lung progenitors as organoids derived from single adult human alveolar epithelial type II (AT2) or KRT5+ basal cells. AT2 organoids were able to differentiate into AT1 cells, and basal cell organoids developed lumens lined with differentiated club and ciliated cells. Single-cell analysis of KRT5+ cells in basal organoids revealed a distinct population of ITGA6+ITGB4+ mitotic cells, whose offspring further segregated into a TNFRSF12Ahi subfraction that comprised about ten per cent of KRT5+ basal cells. This subpopulation formed clusters within terminal bronchioles and exhibited enriched clonogenic organoid growth activity. We created distal lung organoids with apical-out polarity to present ACE2 on the exposed external surface, facilitating infection of AT2 and basal cultures with SARS-CoV-2 and identifying club cells as a target population. This long-term, feeder-free culture of human distal lung organoids, coupled with single-cell analysis, identifies functional heterogeneity among basal cells and establishes a facile in vitro organoid model of human distal lung infections, including COVID-19-associated pneumonia.
Asunto(s)
COVID-19/virología , Pulmón/citología , Modelos Biológicos , Organoides/citología , Organoides/virología , SARS-CoV-2/fisiología , Técnicas de Cultivo de Tejidos , Células Epiteliales Alveolares/citología , Células Epiteliales Alveolares/metabolismo , Células Epiteliales Alveolares/virología , COVID-19/metabolismo , COVID-19/patología , Diferenciación Celular , División Celular , Células Clonales/citología , Células Clonales/metabolismo , Células Clonales/virología , Humanos , Técnicas In Vitro , Subtipo H1N1 del Virus de la Influenza A/crecimiento & desarrollo , Subtipo H1N1 del Virus de la Influenza A/fisiología , Integrina alfa6/análisis , Integrina beta4/análisis , Queratina-5/análisis , Organoides/metabolismo , Neumonía Viral/metabolismo , Neumonía Viral/patología , Neumonía Viral/virología , SARS-CoV-2/crecimiento & desarrollo , Análisis de la Célula Individual , Receptor de TWEAK/análisisRESUMEN
The distal lung contains terminal bronchioles and alveoli that facilitate gas exchange and is affected by disorders including interstitial lung disease, cancer, and SARS-CoV-2-associated COVID-19 pneumonia. Investigations of these localized pathologies have been hindered by a lack of 3D in vitro human distal lung culture systems. Further, human distal lung stem cell identification has been impaired by quiescence, anatomic divergence from mouse and lack of lineage tracing and clonogenic culture. Here, we developed robust feeder-free, chemically-defined culture of distal human lung progenitors as organoids derived clonally from single adult human alveolar epithelial type II (AT2) or KRT5 + basal cells. AT2 organoids exhibited AT1 transdifferentiation potential, while basal cell organoids progressively developed lumens lined by differentiated club and ciliated cells. Organoids consisting solely of club cells were not observed. Upon single cell RNA-sequencing (scRNA-seq), alveolar organoids were composed of proliferative AT2 cells; however, basal organoid KRT5 + cells contained a distinct ITGA6 + ITGB4 + mitotic population whose proliferation segregated to a TNFRSF12A hi subfraction. Clonogenic organoid growth was markedly enriched within the TNFRSF12A hi subset of FACS-purified ITGA6 + ITGB4 + basal cells from human lung or derivative organoids. In vivo, TNFRSF12A + cells comprised ~10% of KRT5 + basal cells and resided in clusters within terminal bronchioles. To model COVID-19 distal lung disease, we everted the polarity of basal and alveolar organoids to rapidly relocate differentiated club and ciliated cells from the organoid lumen to the exterior surface, thus displaying the SARS-CoV-2 receptor ACE2 on the outwardly-facing apical aspect. Accordingly, basal and AT2 apical-out organoids were infected by SARS-CoV-2, identifying club cells as a novel target population. This long-term, feeder-free organoid culture of human distal lung alveolar and basal stem cells, coupled with single cell analysis, identifies unsuspected basal cell functional heterogeneity and exemplifies progenitor identification within a slowly proliferating human tissue. Further, our studies establish a facile in vitro organoid model for human distal lung infectious diseases including COVID-19-associated pneumonia.
RESUMEN
B cells are capable of a wide range of effector functions including antibody secretion, antigen presentation, cytokine production, and generation of immunological memory. A consistent strategy for classifying human B cells by using surface molecules is essential to harness this functional diversity for clinical translation. We developed a highly multiplexed screen to quantify the co-expression of 351 surface molecules on millions of human B cells. We identified differentially expressed molecules and aligned their variance with isotype usage, VDJ sequence, metabolic profile, biosynthesis activity, and signaling response. Based on these analyses, we propose a classification scheme to segregate B cells from four lymphoid tissues into twelve unique subsets, including a CD45RB+CD27- early memory population, a class-switched CD39+ tonsil-resident population, and a CD19hiCD11c+ memory population that potently responds to immune activation. This classification framework and underlying datasets provide a resource for further investigations of human B cell identity and function.
Asunto(s)
Subgrupos de Linfocitos B/clasificación , Subgrupos de Linfocitos B/inmunología , Isotipos de Inmunoglobulinas/metabolismo , Proteínas de la Membrana/metabolismo , 5'-Nucleotidasa/metabolismo , Apirasa/metabolismo , Antígeno CD11c/metabolismo , Femenino , Proteínas Ligadas a GPI/metabolismo , Humanos , Memoria Inmunológica/inmunología , Antígenos Comunes de Leucocito/metabolismo , Persona de Mediana Edad , Transducción de Señal/inmunología , Receptor fas/metabolismoRESUMEN
Accurate prediction of antigen presentation by human leukocyte antigen (HLA) class II molecules would be valuable for vaccine development and cancer immunotherapies. Current computational methods trained on in vitro binding data are limited by insufficient training data and algorithmic constraints. Here we describe MARIA (major histocompatibility complex analysis with recurrent integrated architecture; https://maria.stanford.edu/ ), a multimodal recurrent neural network for predicting the likelihood of antigen presentation from a gene of interest in the context of specific HLA class II alleles. In addition to in vitro binding measurements, MARIA is trained on peptide HLA ligand sequences identified by mass spectrometry, expression levels of antigen genes and protease cleavage signatures. Because it leverages these diverse training data and our improved machine learning framework, MARIA (area under the curve = 0.89-0.92) outperformed existing methods in validation datasets. Across independent cancer neoantigen studies, peptides with high MARIA scores are more likely to elicit strong CD4+ T cell responses. MARIA allows identification of immunogenic epitopes in diverse cancers and autoimmune disease.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Biología Computacional/métodos , Antígenos de Histocompatibilidad Clase II/genética , Presentación de Antígeno , Aprendizaje Profundo , Antígenos de Histocompatibilidad Clase II/química , Humanos , Células K562 , Espectrometría de Masas , Redes Neurales de la Computación , Péptidos/metabolismo , Análisis de Secuencia de ARNRESUMEN
During the first 5 years of life, children are especially vulnerable to infection-related morbidity and mortality. Conversely, the Hygiene Hypothesis suggests that a lack of exposure to infectious agents early in life could explain the increasing incidence of allergies and autoimmunity in high-income countries. Understanding these phenomena, however, is hampered by a lack of comprehensive, direct immune monitoring in children with differing degrees of microbial exposure. Using mass cytometry, we provide an in-depth profile of the peripheral blood mononuclear cells (PBMCs) of children in regions at the extremes of exposure: the San Francisco Bay Area, USA and an economically poor district of Dhaka, Bangladesh. Despite variability in clinical health, functional characteristics of PBMCs were similar in Bangladeshi and American children at 1 year of age. However, by 2-3 years of age, Bangladeshi children's immune cells often demonstrated altered activation and cytokine production profiles upon stimulation with PMA-ionomycin, with an overall immune trajectory more in line with American adults. Conversely, immune responses in children from the US remained steady. Using principal component analysis, donor location, ethnic background, and cytomegalovirus infection status were found to account for some of the variation identified among samples. Within Bangladeshi 1-year-olds, stunting (as measured by height-for-age z-scores) was found to be associated with IL-8 and TGFß expression in PMA-ionomycin stimulated samples. Combined, these findings provide important insights into the immune systems of children in high vs. low microbial exposure environments and suggest an important role for IL-8 and TGFß in mitigating the microbial challenges faced by the Bangladeshi children.
Asunto(s)
Diferenciación Celular/inmunología , Linfocitos T/inmunología , Bangladesh , Niño , Preescolar , Citocinas/inmunología , Femenino , Humanos , Lactante , Interleucina-8/inmunología , Leucocitos Mononucleares/inmunología , Activación de Linfocitos/inmunología , Masculino , Factor de Crecimiento Transformador beta/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Estados UnidosRESUMEN
Somatic mutations in cancer are a potential source of cancer specific neoantigens. Acute myeloid leukemia (AML) has common recurrent mutations shared between patients in addition to private mutations specific to individuals. We hypothesized that neoantigens derived from recurrent shared mutations would be attractive targets for future immunotherapeutic approaches. Here we sought to study the HLA Class I and II immunopeptidome of thirteen primary AML tumor samples and two AML cell lines (OCI-AML3 and MV4-11) using mass spectrometry to evaluate for endogenous mutation-bearing HLA ligands from common shared AML mutations. We identified two endogenous, mutation-bearing HLA Class I ligands from nucleophosmin (NPM1). The ligands, AVEEVSLRK from two patient samples and C(cys)LAVEEVSL from OCI-AML3, are predicted to bind the common HLA haplotypes, HLA-A*03:01 and HLA-A*02:01 respectively. Since NPM1 is mutated in approximately one-third of patients with AML, the finding of endogenous HLA ligands from mutated NPM1 supports future studies evaluating immunotherapeutic approaches against this shared target, for this subset of patients with AML.
Asunto(s)
Presentación de Antígeno/genética , Antígenos de Neoplasias/inmunología , Antígenos HLA/inmunología , Leucemia Mieloide Aguda/inmunología , Proteínas Nucleares/genética , Conjuntos de Datos como Asunto , Mutación del Sistema de Lectura/inmunología , Humanos , Leucemia Mieloide Aguda/genética , Proteínas Nucleares/inmunología , Nucleofosmina , Proteómica/métodosRESUMEN
In mass cytometry, sample loss is of considerable concern due to the relative inefficiency of cell event collection compared to similar techniques such as flow cytometry. Cell stimulation and the harsh conditions required in the later stages of certain sample preparations also contribute to cell loss. Low starting cell numbers are especially susceptible to these effects, potentially limiting the ability to use mass cytometry. Here is presented a live cell barcoding scheme and additional efficiency methods to improve recovery and achieve consistent staining for small samples.
Asunto(s)
Procesamiento Automatizado de Datos/métodos , Citometría de Flujo/métodos , Leucocitos Mononucleares/citología , Espectrometría de Masas/métodos , Análisis de la Célula Individual/métodos , Coloración y Etiquetado/métodos , Separación Celular , Humanos , Metales/química , Manejo de EspecímenesRESUMEN
Antigenic exposures at epithelial sites in infancy and early childhood are thought to influence the maturation of humoral immunity and modulate the risk of developing immunoglobulin E (IgE)-mediated allergic disease. How different kinds of environmental exposures influence B cell isotype switching to IgE, IgG, or IgA, and the somatic mutation maturation of these antibody pools, is not fully understood. We sequenced antibody repertoires in longitudinal blood samples in a birth cohort from infancy through the first 3 years of life and found that, whereas IgG and IgA show linear increases in mutational maturation with age, IgM and IgD mutations are more closely tied to pathogen exposure. IgE mutation frequencies are primarily increased in children with impaired skin barrier conditions such as eczema, suggesting that IgE affinity maturation could provide a mechanistic link between epithelial barrier failure and allergy development.
Asunto(s)
Enfermedades Transmisibles/inmunología , Ambiente , Receptores de Antígenos de Linfocitos B/metabolismo , Adulto , Envejecimiento , Anticuerpos/genética , Antígenos/inmunología , Linfocitos B/inmunología , Carbanilidas , Preescolar , Células Clonales , Eccema/inmunología , Composición Familiar , Femenino , Humanos , Hipersensibilidad/inmunología , Cambio de Clase de Inmunoglobulina , Inmunoglobulina E/metabolismo , Cadenas Pesadas de Inmunoglobulina/genética , Región Variable de Inmunoglobulina/genética , Lactante , Masculino , Hipermutación Somática de Inmunoglobulina , Vacunas/inmunologíaRESUMEN
Chronically undernourished children become stunted during their first 2 years and thereafter bear burdens of ill health for the rest of their lives. Contributors to stunting include poor nutrition and exposure to pathogens, and parental history may also play a role. However, the epigenetic impact of a poor environment on young children is largely unknown. Here we show the unfolding pattern of histone H3 lysine 4 trimethylation (H3K4me3) in children and mothers living in an urban slum in Dhaka, Bangladesh. A pattern of chromatin modification in blood cells of stunted children emerges over time and involves a global decrease in methylation at canonical locations near gene start sites and increased methylation at ectopic sites throughout the genome. This redistribution occurs at metabolic and immune genes and was specific for H3K4me3, as it was not observed for histone H3 lysine 27 acetylation in the same samples. Methylation changes in stunting globally resemble changes that occur in vitro in response to altered methylation capacity, suggesting that reduced levels of one-carbon nutrients in the diet play a key role in stunting in this population. A network of differentially expressed genes in stunted children reveals effects on chromatin modification machinery, including turnover of H3K4me3, as well as posttranscriptional gene regulation affecting immune response pathways and lipid metabolism. Consistent with these changes, reduced expression of the endocytic receptor gene LDL receptor 1 (LRP1) is a driver of stunting in a mouse model, suggesting a target for intervention.
Asunto(s)
Histonas/genética , Desnutrición/genética , Animales , Epigénesis Genética , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Desnutrición/metabolismo , Metilación , RatonesRESUMEN
There are fundamental differences between humans and the animals we typically use to study the immune system. We have learned much from genetically manipulated and inbred animal models, but instances in which these findings have been successfully translated to human immunity have been rare. Embracing the genetic and environmental diversity of humans can tell us about the fundamental biology of immune cell types and the elasticity of the immune system. Although people are much more immunologically diverse than conventionally housed animal models, tools and technologies are now available that permit high-throughput analysis of human samples, including both blood and tissues, which will give us deep insights into human immunity in health and disease. As we gain a more detailed picture of the human immune system, we can build more sophisticated models to better reflect this complexity, both enabling the discovery of new immunological mechanisms and facilitating translation into the clinic.