RESUMEN
Human immunodeficiency virus 1 (HIV-1) infection is characterized by a dynamic and persistent state of viral replication that overwhelms the host immune system in the absence of antiretroviral therapy (ART). The impact of prolonged treatment on the antiviral efficacy of HIV-1-specific CD8+ T cells has nonetheless remained unknown. Here, we used single-cell technologies to address this issue in a cohort of aging individuals infected early during the pandemic and subsequently treated with continuous ART. Our data showed that long-term ART was associated with a process of clonal succession, which effectively rejuvenated HIV-1-specific CD8+ T cell populations in the face of immune senescence. Tracking individual transcriptomes further revealed that initially dominant CD8+ T cell clonotypes displayed signatures of exhaustion and terminal differentiation, whereas newly dominant CD8+ T cell clonotypes displayed signatures of early differentiation and stemness associated with natural control of viral replication. These findings reveal a degree of immune resilience that could inform adjunctive treatments for HIV-1.
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Linfocitos T CD8-positivos , Infecciones por VIH , VIH-1 , Replicación Viral , Linfocitos T CD8-positivos/inmunología , VIH-1/inmunología , VIH-1/fisiología , Humanos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/inmunología , Infecciones por VIH/virología , Replicación Viral/efectos de los fármacos , Masculino , Persona de Mediana Edad , Femenino , Terapia Antirretroviral Altamente Activa , Antirretrovirales/uso terapéutico , Análisis de la Célula Individual , Diferenciación Celular/inmunologíaRESUMEN
We describe humans with rare biallelic loss-of-function PTCRA variants impairing pre-α T cell receptor (pre-TCRα) expression. Low circulating naive αß T cell counts at birth persisted over time, with normal memory αß and high γδ T cell counts. Their TCRα repertoire was biased, which suggests that noncanonical thymic differentiation pathways can rescue αß T cell development. Only a minority of these individuals were sick, with infection, lymphoproliferation, and/or autoimmunity. We also report that 1 in 4000 individuals from the Middle East and South Asia are homozygous for a common hypomorphic PTCRA variant. They had normal circulating naive αß T cell counts but high γδ T cell counts. Although residual pre-TCRα expression drove the differentiation of more αß T cells, autoimmune conditions were more frequent in these patients compared with the general population.
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Autoinmunidad , Linfocitos Intraepiteliales , Glicoproteínas de Membrana , Receptores de Antígenos de Linfocitos T alfa-beta , Humanos , Autoinmunidad/genética , Diferenciación Celular , Homocigoto , Linfocitos Intraepiteliales/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Glicoproteínas de Membrana/genética , Mutación con Pérdida de Función , Recuento de Linfocitos , Alelos , Infecciones/inmunología , Trastornos Linfoproliferativos/inmunología , Linaje , Masculino , Femenino , Persona de Mediana Edad , Anciano , Anciano de 80 o más AñosRESUMEN
Norovirus infection can cause gastrointestinal disease in humans. Development of therapies and vaccines against norovirus have been limited by the lack of a suitable and reliable animal model. Here we established rhesus macaques as an animal model for human norovirus infection. We show that rhesus macaques are susceptible to oral infection with human noroviruses from two different genogroups. Variation in duration of virus shedding (days to weeks) between animals, evolution of the virus over the time of infection, induction of virus-specific adaptive immune responses, susceptibility to reinfection and preferential replication of norovirus in the jejunum of rhesus macaques was similar to infection reported in humans. We found minor pathological signs and changes in epithelial cell surface glycosylation patterns in the small intestine during infection. Detection of viral protein and RNA in intestinal biopsies confirmed the presence of the virus in chromogranin A-expressing epithelial cells, as it does in humans. Thus, rhesus macaques are a promising non-human primate model to evaluate vaccines and therapeutics against norovirus disease.
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Infecciones por Caliciviridae , Norovirus , Vacunas , Humanos , Animales , Macaca mulatta , Intestino DelgadoRESUMEN
The environmental impacts of global warming driven by methane (CH4) emissions have catalyzed significant research initiatives in developing novel technologies that enable proactive and rapid detection of CH4. Several data-driven machine learning (ML) models were tested to determine how well they identified fugitive CH4 and its related intensity in the affected areas. Various meteorological characteristics, including wind speed, temperature, pressure, relative humidity, water vapor, and heat flux, were included in the simulation. We used the ensemble learning method to determine the best-performing weighted ensemble ML models built upon several weaker lower-layer ML models to (i) detect the presence of CH4 as a classification problem and (ii) predict the intensity of CH4 as a regression problem. The classification model performance for CH4 detection was evaluated using accuracy, F1 score, Matthew's Correlation Coefficient (MCC), and the area under the receiver operating characteristic curve (AUC ROC), with the top-performing model being 97.2%, 0.972, 0.945 and 0.995, respectively. The R 2 score was used to evaluate the regression model performance for CH4 intensity prediction, with the R 2 score of the best-performing model being 0.858. The ML models developed in this study for fugitive CH4 detection and intensity prediction can be used with fixed environmental sensors deployed on the ground or with sensors mounted on unmanned aerial vehicles (UAVs) for mobile detection.
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Key Clinical Message: Nibima and Immunim manages mild COVID-19 in 7 days. Abstract: Coronavirus Disease 2019 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) can lead to severe complications and deaths. The search for phytotherapeutic agents to augment the fight against the current COVID-19 pandemic is therefore of highest priority. A 52-year-old female with no history of chronic illness presented to our clinic facility with a 3 days loss of smell and headache which persisted after self-medication. The patient tested positive for COVID-19 in the SARS-CoV-2 Ag test as well as the Typhoid rapid antibody test. Routine laboratory tests were not remarkable. A 60 mL three times daily dose of Nibima and 5 mL in 40 mL of warm water dose of Immunim were given to the patient for 7 days. Patient recovered sense of smell and regained appetite but cough although reduced persisted. She also tested negative for COVID-19 after 7 days treatment. This case is the first documented case of COVID-19 management with herbal medicines in Ghana. We strongly suggest a larger control trial on these products to ascertain these findings to repurpose them as viable treatments for COVID-19.
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As SARS-CoV-2 variants continue evolving, testing updated vaccines in non-human primates remains important for guiding human clinical practice. To date, such studies have focused on antibody titers and antigen-specific B and T cell frequencies. Here, we extend our understanding by integrating innate and adaptive immune responses to mRNA-1273 vaccination in rhesus macaques. We sorted innate immune cells from a pre-vaccine time point, as well as innate immune cells and antigen-specific peripheral B and T cells two weeks after each of two vaccine doses and used single-cell sequencing to assess the transcriptomes and adaptive immune receptors of each cell. We show that a subset of S-specific T cells expresses cytokines critical for activating innate responses, with a concomitant increase in CCR5-expressing intermediate monocytes and a shift of natural killer cells to a more cytotoxic phenotype. The second vaccine dose, administered 4 weeks after the first, elicits an increase in circulating germinal center-like B cells 2 weeks later, which are more clonally expanded and enriched for epitopes in the receptor binding domain. Both doses stimulate inflammatory response genes associated with elevated antibody production. Overall, we provide a comprehensive picture of bidirectional signaling between innate and adaptive components of the immune system and suggest potential mechanisms for the enhanced response to secondary exposure.
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Antígenos de Grupos Sanguíneos , COVID-19 , Animales , Humanos , Vacunas contra la COVID-19 , Macaca mulatta , SARS-CoV-2 , COVID-19/prevención & control , Vacunación , Anticuerpos AntiviralesRESUMEN
Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related Th cells (type 17 cells) and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo. By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The phenotypes and epigenomes of CCR6+ cells are stable across cell divisions under noninflammatory conditions. Nonetheless, activation in polarizing and nonpolarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the type 17 continuum to yield the unusual plasticity ascribed to type 17 cells.
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Enfermedades Autoinmunes , Células Th17 , Humanos , Diferenciación Celular , Fenotipo , Receptores CCR6/genética , Células TH1/metabolismoRESUMEN
Th17 cells have been investigated in mice primarily for their contributions to autoimmune diseases. However, the pathways of differentiation of Th17 and related (type 17) cells and the structure of the type 17 memory population in humans are not well understood; such understanding is critical for manipulating these cells in vivo . By exploiting differences in levels of surface CCR6, we found that human type 17 memory cells, including individual T cell clonotypes, form an elongated continuum of type 17 character along which cells can be driven by increasing RORγt. This continuum includes cells preserved within the memory pool with potentials that reflect the early preferential activation of multiple over single lineages. The CCR6 + cells' phenotypes and epigenomes are stable across cell divisions under homeostatic conditions. Nonetheless, activation in polarizing and non-polarizing conditions can yield additional functionalities, revealing, respectively, both environmentally induced and imprinted mechanisms that contribute differentially across the continuum to yield the unusual plasticity ascribed to type 17 cells.
RESUMEN
Rare CD4 T cells that contain HIV under antiretroviral therapy represent an important barrier to HIV cure1-3, but the infeasibility of isolating and characterizing these cells in their natural state has led to uncertainty about whether they possess distinctive attributes that HIV cure-directed therapies might exploit. Here we address this challenge using a microfluidic technology that isolates the transcriptomes of HIV-infected cells based solely on the detection of HIV DNA. HIV-DNA+ memory CD4 T cells in the blood from people receiving antiretroviral therapy showed inhibition of six transcriptomic pathways, including death receptor signalling, necroptosis signalling and antiproliferative Gα12/13 signalling. Moreover, two groups of genes identified by network co-expression analysis were significantly associated with HIV-DNA+ cells. These genes (n = 145) accounted for just 0.81% of the measured transcriptome and included negative regulators of HIV transcription that were higher in HIV-DNA+ cells, positive regulators of HIV transcription that were lower in HIV-DNA+ cells, and other genes involved in RNA processing, negative regulation of mRNA translation, and regulation of cell state and fate. These findings reveal that HIV-infected memory CD4 T cells under antiretroviral therapy are a distinctive population with host gene expression patterns that favour HIV silencing, cell survival and cell proliferation, with important implications for the development of HIV cure strategies.
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Linfocitos T CD4-Positivos , Regulación Viral de la Expresión Génica , Infecciones por VIH , VIH-1 , Latencia del Virus , Humanos , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/virología , Proliferación Celular/efectos de los fármacos , Supervivencia Celular/efectos de los fármacos , ADN Viral/aislamiento & purificación , Regulación Viral de la Expresión Génica/efectos de los fármacos , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/genética , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-1/efectos de los fármacos , VIH-1/genética , VIH-1/aislamiento & purificación , VIH-1/patogenicidad , Memoria Inmunológica , Microfluídica , Necroptosis/efectos de los fármacos , Transducción de Señal/efectos de los fármacos , Transcriptoma/efectos de los fármacos , Latencia del Virus/efectos de los fármacos , Antirretrovirales/farmacología , Antirretrovirales/uso terapéuticoRESUMEN
Modifications to vaccine delivery that increase serum antibody longevity are of great interest for maximizing efficacy. We have previously shown that a delayed fractional (DFx) dosing schedule (0-1-6 month) - using AS01B-adjuvanted RH5.1 malaria antigen - substantially improves serum IgG durability as compared with monthly dosing (0-1-2 month; NCT02927145). However, the underlying mechanism and whether there are wider immunological changes with DFx dosing were unclear. Here, PfRH5-specific Ig and B cell responses were analyzed in depth through standardized ELISAs, flow cytometry, systems serology, and single-cell RNA-Seq (scRNA-Seq). Data indicate that DFx dosing increases the magnitude and durability of circulating PfRH5-specific B cells and serum IgG1. At the peak antibody magnitude, DFx dosing was distinguished by a systems serology feature set comprising increased FcRn binding, IgG avidity, and proportion of G2B and G2S2F IgG Fc glycans, alongside decreased IgG3, antibody-dependent complement deposition, and proportion of G1S1F IgG Fc glycan. Concomitantly, scRNA-Seq data show a higher CDR3 percentage of mutation from germline and decreased plasma cell gene expression in circulating PfRH5-specific B cells. Our data, therefore, reveal a profound impact of DFx dosing on the humoral response and suggest plausible mechanisms that could enhance antibody longevity, including improved FcRn binding by serum Ig and a potential shift in the underlying cellular response from circulating short-lived plasma cells to nonperipheral long-lived plasma cells.
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Vacunas contra la Malaria , Humanos , Antígenos de Protozoos , Linfocitos B , Linfocitos , Inmunoglobulina GRESUMEN
PURPOSE: The Research on Obesity and Diabetes among African Migrants (RODAM) prospective (RODAM-Pros) cohort study was established to identify key changes in environmental exposures and epigenetic modifications driving the high burden of cardiovascular disease (CVD) risk among sub-Saharan African migrants. PARTICIPANTS: All the participants in the RODAM cross-sectional study that completed the baseline assessment (n=5114) were eligible for the follow-up of which 2165 participants (n=638 from rural-Ghana, n=608 from urban-Ghana, and n=919 Ghanaian migrants in Amsterdam, the Netherlands) were included in the RODAM-Pros cohort study. Additionally, we included a subsample of European-Dutch (n=2098) to enable a comparison to be made between Ghanaian migrants living in the Netherlands and the European-Dutch host population. FINDINGS TO DATE: Follow-up data have been collected on demographics, socioeconomic status, medical history, psychosocial environment, lifestyle factors, nutrition, anthropometrics, blood pressure, fasting blood, urine and stool samples. Biochemical analyses included glucose metabolism, lipid profile, electrolytes and renal function, liver metabolism and inflammation. In a subsample, we assessed DNA methylation patterns using Infinium 850K DNA Methylation BeadChip. Baseline results indicated that migrants have higher prevalence of CVD risk factors than non-migrants. Epigenome-wide association studies suggest important differences in DNA methylation between migrants and non-migrants. The follow-up study will shed further light on key-specific environmental exposures and epigenetic modifications contributing to the high burden of CVD risk among sub-Saharan African migrants. FUTURE PLANS: Follow-up is planned at 5-year intervals, baseline completed in 2015 and first follow-up completed in 2021.
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Enfermedades Cardiovasculares , Diabetes Mellitus , Migrantes , Humanos , Estudios Transversales , Estudios de Cohortes , Ghana/epidemiología , Estudios de Seguimiento , Estudios Prospectivos , Europa (Continente)/epidemiología , Prevalencia , Obesidad/epidemiología , Obesidad/complicaciones , Enfermedades Cardiovasculares/epidemiología , Enfermedades Cardiovasculares/etiología , Pueblo Africano , Factores de RiesgoRESUMEN
Although combination antiretroviral therapy (ART) blocks HIV replication, it is not curative because infected CD4+ T cells that carry intact, infectious proviruses persist. Understanding the behavior of clones of infected T cells is important for understanding the stability of the reservoir; however, the stabilities of clones of infected T cells in persons on long-term ART are not well defined. We determined the relative stabilities of clones of infected and uninfected CD4+ T cells over time intervals of one to four years in three individuals who had been on ART for 9-19 years. The largest clones of uninfected T cells were larger than the largest clones of infected T cells. Clones of infected CD4+ T cells were more stable than clones of uninfected CD4+ T cells of a similar size. Individual clones of CD4+ T cells carrying intact, infectious proviruses can expand, contract, or remain stable over time.
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Infecciones por VIH , VIH-1 , Linfocitos T CD4-Positivos , Células Clonales , ADN Viral , Infecciones por VIH/tratamiento farmacológico , VIH-1/genética , Humanos , Provirus/genéticaRESUMEN
The dynamics of T-cell receptor (TCR)selection in chronic HIV-1 infection, and its association with clinical outcome, is well documented for an array of MHC-peptide complexes and disease stages. However, the factors that may contribute to the selection and expansion of CD8+ T-cells in chronic HIV-2 infection, especially at the clonal level remain unclear. To address this question, we undertook a detailed molecular characterization of the clonotypic architecture of an HLA-B*3501 restricted Gag-specific CD8+ T-cell response in donors chronically infected with HIV-2 using a combination of flow cytometry, tetramer-specific CD8+ TCR clonotyping, and in vitro assays. We show that the response to the NY9 epitope is hierarchical and narrow in terms of T-cell receptor-alpha (TCRA) and -beta (TCRB) gene usage yet clonotypically diverse. Furthermore, clonotypic dominance in shared origin CTL clones was associated with a greater magnitude of cytokine production and antigen sensitivity at limiting antigen dilution as well as enhanced cross-reactivity for known HIV-2 variants. Hence, our data suggest that effector mobilization and expansion in human chronic HIV-2 infection may be linked to the qualitative features of specific CD8+ T-cell clonotypes, which could have implications for viral control and disease outcome.
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Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , Infecciones por VIH/virología , VIH-2/fisiología , Especificidad del Receptor de Antígeno de Linfocitos T , Productos del Gen gag del Virus de la Inmunodeficiencia Humana/inmunología , Secuencias de Aminoácidos , Linfocitos T CD8-positivos/metabolismo , Enfermedad Crónica , Secuencia Conservada , Epítopos de Linfocito T/inmunología , Infecciones por VIH/metabolismo , Interacciones Huésped-Patógeno/inmunología , Humanos , Activación de Linfocitos/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/química , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismoRESUMEN
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOCs) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identified four receptor binding domain-targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 23 variants, including the B.1.1.7, B.1.351, P.1, B.1.429, B.1.526, and B.1.617 VOCs. Two antibodies are ultrapotent, with subnanomolar neutralization titers [half-maximal inhibitory concentration (IC50) 0.3 to 11.1 nanograms per milliliter; IC80 1.5 to 34.5 nanograms per milliliter). We define the structural and functional determinants of binding for all four VOC-targeting antibodies and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting their potential in mitigating resistance development.
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Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , COVID-19/inmunología , SARS-CoV-2/inmunología , SARS-CoV-2/patogenicidad , Glicoproteína de la Espiga del Coronavirus/inmunología , Enzima Convertidora de Angiotensina 2/antagonistas & inhibidores , Enzima Convertidora de Angiotensina 2/metabolismo , Anticuerpos Neutralizantes/química , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/química , Anticuerpos Antivirales/metabolismo , Afinidad de Anticuerpos , Reacciones Antígeno-Anticuerpo , COVID-19/virología , Humanos , Evasión Inmune , Fragmentos Fab de Inmunoglobulinas/inmunología , Fragmentos Fab de Inmunoglobulinas/metabolismo , Mutación , Pruebas de Neutralización , Dominios Proteicos , Receptores de Coronavirus/antagonistas & inhibidores , Receptores de Coronavirus/metabolismo , SARS-CoV-2/genética , Glicoproteína de la Espiga del Coronavirus/química , Glicoproteína de la Espiga del Coronavirus/genética , Glicoproteína de la Espiga del Coronavirus/metabolismoRESUMEN
The development of follicular helper CD4 T (TFH) cells is a dynamic process resulting in a heterogenous pool of TFH subsets. However, the cellular and molecular determinants of this heterogeneity and the possible mechanistic links between them is not clear. We found that human TFH differentiation is associated with significant changes in phenotypic, chemokine, functional, metabolic and transcriptional profile. Furthermore, this differentiation was associated with distinct positioning to follicular proliferating B cells. Single-cell T cell receptor (TCR) clonotype analysis indicated the transitioning toward PD-1hiCD57hi phenotype. Furthermore, the differentiation of TFH cells was associated with significant reduction in TCR level and drastic changes in immunological synapse formation. TFH synapse lacks a tight cSMAC (central supra molecular activation Cluster) but displays the TCR in peripheral microclusters, which are potentially advantageous in the ability of germinal center (GC) B cells to receive necessary help. Our data reveal significant aspects of human TFH heterogeneity and suggest that the PD-1hiCD57hi TFH cells, in particular, are endowed with distinctive programming and spatial positioning for optimal GC B cell help.
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Diferenciación Celular/genética , Linaje de la Célula/inmunología , Receptores de Antígenos de Linfocitos T/genética , Células T Auxiliares Foliculares/inmunología , Linfocitos T CD4-Positivos/inmunología , Antígenos CD57/genética , Comunicación Celular/inmunología , Diferenciación Celular/inmunología , Linaje de la Célula/genética , Quimiocinas/genética , Centro Germinal/inmunología , Centro Germinal/metabolismo , Humanos , Sinapsis Inmunológicas/genética , Sinapsis Inmunológicas/inmunología , Activación de Linfocitos/inmunología , Fenotipo , Receptor de Muerte Celular Programada 1/genética , Receptores de Antígenos de Linfocitos T/inmunología , Células T Auxiliares Foliculares/metabolismo , Subgrupos de Linfocitos T/inmunologíaRESUMEN
An effective vaccine for respiratory syncytial virus (RSV) is an unrealized public health goal. A single dose of the prefusion-stabilized fusion (F) glycoprotein subunit vaccine (DS-Cav1) substantially increases serum-neutralizing activity in healthy adults. We sought to determine whether DS-Cav1 vaccination induces a repertoire mirroring the pre-existing diversity from natural infection or whether antibody lineages targeting specific epitopes predominate. We evaluated RSV F-specific B cell responses before and after vaccination in six participants using complementary B cell sequencing methodologies and identified 555 clonal lineages. DS-Cav1-induced lineages recognized the prefusion conformation of F (pre-F) and were genetically diverse. Expressed antibodies recognized all six antigenic sites on the pre-F trimer. We identified 34 public clonotypes, and structural analysis of two antibodies from a predominant clonotype revealed a common mode of recognition. Thus, vaccination with DS-Cav1 generates a diverse polyclonal response targeting the antigenic sites on pre-F, supporting the development and advanced testing of pre-F-based vaccines against RSV.
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Anticuerpos Antivirales/inmunología , Formación de Anticuerpos/inmunología , Infecciones por Virus Sincitial Respiratorio/inmunología , Vacunas contra Virus Sincitial Respiratorio/inmunología , Virus Sincitial Respiratorio Humano/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Neutralizantes/inmunología , Línea Celular , Línea Celular Tumoral , Niño , Preescolar , Estudios de Cohortes , Epítopos/inmunología , Femenino , Células HEK293 , Humanos , Lactante , Recién Nacido , Masculino , Persona de Mediana Edad , Vacunación/métodos , Proteínas Virales de Fusión/inmunología , Adulto JovenRESUMEN
The epidemic spread of Zika virus (ZIKV), associated with devastating neurologic syndromes, has driven the development of multiple ZIKV vaccines candidates. An effective vaccine should induce ZIKV-specific T cell responses, which are shown to improve the establishment of humoral immunity and contribute to viral clearance. Here we investigated how previous immunization against Japanese encephalitis virus (JEV) and yellow fever virus (YFV) influences T cell responses elicited by a Zika purified-inactivated virus (ZPIV) vaccine. We demonstrate that three doses of ZPIV vaccine elicited robust CD4 T cell responses to ZIKV structural proteins, while ZIKV-specific CD4 T cells in pre-immunized individuals with JEV vaccine, but not YFV vaccine, were more durable and directed predominantly toward conserved epitopes, which elicited Th1 and Th2 cytokine production. In addition, T cell receptor repertoire analysis revealed preferential expansion of cross-reactive clonotypes between JEV and ZIKV, suggesting that pre-existing immunity against JEV may prime the establishment of stronger CD4 T cell responses to ZPIV vaccination. These CD4 T cell responses correlated with titers of ZIKV-neutralizing antibodies in the JEV pre-vaccinated group, but not in flavivirus-naïve or YFV pre-vaccinated individuals, suggesting a stronger contribution of CD4 T cells in the generation of neutralizing antibodies in the context of JEV-ZIKV cross-reactivity.
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Anticuerpos Antivirales/inmunología , Linfocitos T CD4-Positivos/inmunología , Vacunas contra la Encefalitis Japonesa/inmunología , Virus Zika/inmunología , Anticuerpos Neutralizantes/inmunología , Reacciones Cruzadas , Método Doble Ciego , Virus de la Encefalitis Japonesa (Especie)/inmunología , Humanos , Vacunas de Productos Inactivados/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/inmunología , Infección por el Virus Zika/inmunología , Infección por el Virus Zika/prevención & controlRESUMEN
αß and γδ T cell receptors (TCRs) are highly diverse antigen receptors that define two evolutionarily conserved T cell lineages. We describe a population of γµTCRs found exclusively in non-eutherian mammals that consist of a two-domain (Vγ-Cγ) γ-chain paired to a three-domain (Vµ-Vµj-Cµ) µ-chain. γµTCRs were characterized by restricted diversity in the Vγ and Vµj domains and a highly diverse unpaired Vµ domain. Crystal structures of two distinct γµTCRs revealed the structural basis of the association of the γµTCR heterodimer. The Vµ domain shared the characteristics of a single-domain antibody within which the hypervariable CDR3µ loop suggests a major antigen recognition determinant. We define here the molecular basis underpinning the assembly of a third TCR lineage, the γµTCR.
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Monodelphis/inmunología , Receptores de Antígenos de Linfocitos T/química , Subgrupos de Linfocitos T/inmunología , Animales , Linaje de la Célula , Regiones Determinantes de Complementariedad/química , Cristalografía por Rayos X , Modelos Moleculares , Monodelphis/genética , Conformación Proteica , Dominios Proteicos , Multimerización de Proteína , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta , Receptores de Antígenos de Linfocitos T gamma-deltaRESUMEN
The emergence of highly transmissible SARS-CoV-2 variants of concern (VOC) that are resistant to therapeutic antibodies highlights the need for continuing discovery of broadly reactive antibodies. We identify four receptor-binding domain targeting antibodies from three early-outbreak convalescent donors with potent neutralizing activity against 12 variants including the B.1.1.7 and B.1.351 VOCs. Two of them are ultrapotent, with sub-nanomolar neutralization titers (IC50 <0.0006 to 0.0102 µ g/mL; IC80 < 0.0006 to 0.0251 µ g/mL). We define the structural and functional determinants of binding for all four VOC-targeting antibodies, and show that combinations of two antibodies decrease the in vitro generation of escape mutants, suggesting potential means to mitigate resistance development. These results define the basis of therapeutic cocktails against VOCs and suggest that targeted boosting of existing immunity may increase vaccine breadth against VOCs.