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1.
Annu Rev Immunol ; 37: 547-570, 2019 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-30699000

RESUMEN

Adaptive immune recognition is mediated by antigen receptors on B and T cells generated by somatic recombination during lineage development. The high level of diversity resulting from this process posed technical limitations that previously limited the comprehensive analysis of adaptive immune recognition. Advances over the last ten years have produced data and approaches allowing insights into how T cells develop, evolutionary signatures of recombination and selection, and the features of T cell receptors that mediate epitope-specific binding and T cell activation. The size and complexity of these data have necessitated the generation of novel computational and analytical approaches, which are transforming how T cell immunology is conducted. Here we review the development and application of novel biological, theoretical, and computational methods for understanding T cell recognition and discuss the potential for improved models of receptor:antigen interactions.


Asunto(s)
Biología Computacional/métodos , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Antígenos/inmunología , Antígenos/metabolismo , Diferenciación Celular , Selección Clonal Mediada por Antígenos , Epítopos de Linfocito T/metabolismo , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Activación de Linfocitos , Receptores de Antígenos de Linfocitos T/metabolismo
2.
Cell ; 187(9): 2052-2078, 2024 Apr 25.
Artículo en Inglés | MEDLINE | ID: mdl-38670065

RESUMEN

Adaptive immunity provides protection against infectious and malignant diseases. These effects are mediated by lymphocytes that sense and respond with targeted precision to perturbations induced by pathogens and tissue damage. Here, we review key principles underlying adaptive immunity orchestrated by distinct T cell and B cell populations and their extensions to disease therapies. We discuss the intracellular and intercellular processes shaping antigen specificity and recognition in immune activation and lymphocyte functions in mediating effector and memory responses. We also describe how lymphocytes balance protective immunity against autoimmunity and immunopathology, including during immune tolerance, response to chronic antigen stimulation, and adaptation to non-lymphoid tissues in coordinating tissue immunity and homeostasis. Finally, we discuss extracellular signals and cell-intrinsic programs underpinning adaptive immunity and conclude by summarizing key advances in vaccination and engineering adaptive immune responses for therapeutic interventions. A deeper understanding of these principles holds promise for uncovering new means to improve human health.


Asunto(s)
Inmunidad Adaptativa , Humanos , Animales , Linfocitos B/inmunología , Linfocitos T/inmunología , Autoinmunidad/inmunología
3.
Cell ; 185(4): 603-613.e15, 2022 02 17.
Artículo en Inglés | MEDLINE | ID: mdl-35026152

RESUMEN

SARS-CoV-2 mRNA vaccines induce robust anti-spike (S) antibody and CD4+ T cell responses. It is not yet clear whether vaccine-induced follicular helper CD4+ T (TFH) cell responses contribute to this outstanding immunogenicity. Using fine-needle aspiration of draining axillary lymph nodes from individuals who received the BNT162b2 mRNA vaccine, we evaluated the T cell receptor sequences and phenotype of lymph node TFH. Mining of the responding TFH T cell receptor repertoire revealed a strikingly immunodominant HLA-DPB1∗04-restricted response to S167-180 in individuals with this allele, which is among the most common HLA alleles in humans. Paired blood and lymph node specimens show that while circulating S-specific TFH cells peak one week after the second immunization, S-specific TFH persist at nearly constant frequencies for at least six months. Collectively, our results underscore the key role that robust TFH cell responses play in establishing long-term immunity by this efficacious human vaccine.


Asunto(s)
COVID-19/inmunología , COVID-19/virología , Inmunidad/inmunología , SARS-CoV-2/inmunología , Células T Auxiliares Foliculares/inmunología , Vacunación , Vacunas Sintéticas/inmunología , Vacunas de ARNm/inmunología , Adulto , Linfocitos B/inmunología , Vacuna BNT162/inmunología , COVID-19/sangre , Células Clonales , Estudios de Cohortes , Citocinas/metabolismo , Femenino , Centro Germinal/inmunología , Cadenas beta de HLA-DP/inmunología , Humanos , Epítopos Inmunodominantes/inmunología , Células Jurkat , Ganglios Linfáticos/metabolismo , Masculino , Persona de Mediana Edad , Péptidos/química , Péptidos/metabolismo , Multimerización de Proteína , Receptores de Antígenos de Linfocitos T/metabolismo
4.
Nat Immunol ; 25(9): 1742-1753, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39164477

RESUMEN

The differentiation and specificity of human CD4+ T follicular helper cells (TFH cells) after influenza vaccination have been poorly defined. Here we profiled blood and draining lymph node (LN) samples from human volunteers for over 2 years after two influenza vaccines were administered 1 year apart to define the evolution of the CD4+ TFH cell response. The first vaccination induced an increase in the frequency of circulating TFH (cTFH) and LN TFH cells at week 1 postvaccination. This increase was transient for cTFH cells, whereas the LN TFH cells further expanded during week 2 and remained elevated in frequency for at least 3 months. We observed several distinct subsets of TFH cells in the LN, including pre-TFH cells, memory TFH cells, germinal center (GC) TFH cells and interleukin-10+ TFH cell subsets beginning at baseline and at all time points postvaccination. The shift toward a GC TFH cell phenotype occurred with faster kinetics after the second vaccine compared to the first vaccine. We identified several influenza-specific TFH cell clonal lineages, including multiple responses targeting internal influenza virus proteins, and found that each TFH cell state was attainable within a clonal lineage. Thus, human TFH cells form a durable and dynamic multitissue network.


Asunto(s)
Diferenciación Celular , Centro Germinal , Vacunas contra la Influenza , Gripe Humana , Células T Auxiliares Foliculares , Vacunación , Humanos , Vacunas contra la Influenza/inmunología , Células T Auxiliares Foliculares/inmunología , Gripe Humana/inmunología , Gripe Humana/prevención & control , Centro Germinal/inmunología , Diferenciación Celular/inmunología , Ganglios Linfáticos/inmunología , Adulto , Femenino , Masculino , Persona de Mediana Edad , Interleucina-10/inmunología , Interleucina-10/metabolismo , Memoria Inmunológica/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adulto Joven
5.
Nat Immunol ; 25(9): 1731-1741, 2024 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-39164479

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and mRNA vaccination induce robust CD4+ T cell responses. Using single-cell transcriptomics, here, we evaluated CD4+ T cells specific for the SARS-CoV-2 spike protein in the blood and draining lymph nodes (dLNs) of individuals 3 months and 6 months after vaccination with the BNT162b2 mRNA vaccine. We analyzed 1,277 spike-specific CD4+ T cells, including 238 defined using Trex, a deep learning-based reverse epitope mapping method to predict antigen specificity. Human dLN spike-specific CD4+ follicular helper T (TFH) cells exhibited heterogeneous phenotypes, including germinal center CD4+ TFH cells and CD4+IL-10+ TFH cells. Analysis of an independent cohort of SARS-CoV-2-infected individuals 3 months and 6 months after infection found spike-specific CD4+ T cell profiles in blood that were distinct from those detected in blood 3 months and 6 months after BNT162b2 vaccination. Our findings provide an atlas of human spike-specific CD4+ T cell transcriptional phenotypes in the dLNs and blood following SARS-CoV-2 vaccination or infection.


Asunto(s)
Vacuna BNT162 , Linfocitos T CD4-Positivos , COVID-19 , Ganglios Linfáticos , SARS-CoV-2 , Glicoproteína de la Espiga del Coronavirus , Humanos , COVID-19/inmunología , COVID-19/prevención & control , SARS-CoV-2/inmunología , Glicoproteína de la Espiga del Coronavirus/inmunología , Vacuna BNT162/inmunología , Linfocitos T CD4-Positivos/inmunología , Ganglios Linfáticos/inmunología , Vacunas contra la COVID-19/inmunología , Vacunación , Fenotipo , Femenino , Masculino , Adulto , Persona de Mediana Edad , Vacunas de ARNm/inmunología
6.
Nat Immunol ; 24(9): 1511-1526, 2023 09.
Artículo en Inglés | MEDLINE | ID: mdl-37592015

RESUMEN

Evidence suggests that innate and adaptive cellular responses mediate resistance to the influenza virus and confer protection after vaccination. However, few studies have resolved the contribution of cellular responses within the context of preexisting antibody titers. Here, we measured the peripheral immune profiles of 206 vaccinated or unvaccinated adults to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza. Protection correlated with diverse and polyfunctional CD4+ and CD8+ T, circulating T follicular helper, T helper type 17, myeloid dendritic and CD16+ natural killer (NK) cell subsets. Conversely, increased susceptibility was predominantly attributed to nonspecific inflammatory populations, including γδ T cells and activated CD16- NK cells, as well as TNFα+ single-cytokine-producing CD8+ T cells. Multivariate and predictive modeling indicated that cellular subsets (1) work synergistically with humoral immunity to confer protection, (2) improve model performance over demographic and serologic factors alone and (3) comprise the most important predictive covariates. Together, these results demonstrate that preinfection peripheral cell composition improves the prediction of symptomatic influenza susceptibility over vaccination, demographics or serology alone.


Asunto(s)
Enfermedades Transmisibles , Gripe Humana , Infecciones por Orthomyxoviridae , Orthomyxoviridae , Adulto , Humanos , Linfocitos T CD8-positivos
7.
Nat Immunol ; 24(11): 1890-1907, 2023 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-37749325

RESUMEN

CD8+ T cells provide robust antiviral immunity, but how epitope-specific T cells evolve across the human lifespan is unclear. Here we defined CD8+ T cell immunity directed at the prominent influenza epitope HLA-A*02:01-M158-66 (A2/M158) across four age groups at phenotypic, transcriptomic, clonal and functional levels. We identify a linear differentiation trajectory from newborns to children then adults, followed by divergence and a clonal reset in older adults. Gene profiles in older adults closely resemble those of newborns and children, despite being clonally distinct. Only child-derived and adult-derived A2/M158+CD8+ T cells had the potential to differentiate into highly cytotoxic epitope-specific CD8+ T cells, which was linked to highly functional public T cell receptor (TCR)αß signatures. Suboptimal TCRαß signatures in older adults led to less proliferation, polyfunctionality, avidity and recognition of peptide mutants, although displayed no signs of exhaustion. These data suggest that priming T cells at different stages of life might greatly affect CD8+ T cell responses toward viral infections.


Asunto(s)
Linfocitos T CD8-positivos , Longevidad , Recién Nacido , Humanos , Anciano , Epítopos de Linfocito T/genética , Linfocitos T Citotóxicos , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T/genética
8.
Nat Immunol ; 24(6): 979-990, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37188942

RESUMEN

Antiviral CD8+ T cell immunity depends on the integration of various contextual cues, but how antigen-presenting cells (APCs) consolidate these signals for decoding by T cells remains unclear. Here, we describe gradual interferon-α/interferon-ß (IFNα/ß)-induced transcriptional adaptations that endow APCs with the capacity to rapidly activate the transcriptional regulators p65, IRF1 and FOS after CD4+ T cell-mediated CD40 stimulation. While these responses operate through broadly used signaling components, they induce a unique set of co-stimulatory molecules and soluble mediators that cannot be elicited by IFNα/ß or CD40 alone. These responses are critical for the acquisition of antiviral CD8+ T cell effector function, and their activity in APCs from individuals infected with severe acute respiratory syndrome coronavirus 2 correlates with milder disease. These observations uncover a sequential integration process whereby APCs rely on CD4+ T cells to select the innate circuits that guide antiviral CD8+ T cell responses.


Asunto(s)
Antivirales , COVID-19 , Humanos , Calibración , Células Presentadoras de Antígenos , Linfocitos T CD8-positivos , Antígenos CD40 , Interferón-alfa , Linfocitos T CD4-Positivos
9.
Nat Immunol ; 24(6): 966-978, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-37248417

RESUMEN

High-risk groups, including Indigenous people, are at risk of severe COVID-19. Here we found that Australian First Nations peoples elicit effective immune responses to COVID-19 BNT162b2 vaccination, including neutralizing antibodies, receptor-binding domain (RBD) antibodies, SARS-CoV-2 spike-specific B cells, and CD4+ and CD8+ T cells. In First Nations participants, RBD IgG antibody titers were correlated with body mass index and negatively correlated with age. Reduced RBD antibodies, spike-specific B cells and follicular helper T cells were found in vaccinated participants with chronic conditions (diabetes, renal disease) and were strongly associated with altered glycosylation of IgG and increased interleukin-18 levels in the plasma. These immune perturbations were also found in non-Indigenous people with comorbidities, indicating that they were related to comorbidities rather than ethnicity. However, our study is of a great importance to First Nations peoples who have disproportionate rates of chronic comorbidities and provides evidence of robust immune responses after COVID-19 vaccination in Indigenous people.


Asunto(s)
Vacunas contra la COVID-19 , COVID-19 , Humanos , Vacuna BNT162 , COVID-19/prevención & control , Linfocitos T CD8-positivos , Australia/epidemiología , SARS-CoV-2 , Inmunoglobulina G , Anticuerpos Neutralizantes , Inmunidad , Anticuerpos Antivirales , Vacunación
10.
Cell ; 180(6): 1115-1129.e13, 2020 03 19.
Artículo en Inglés | MEDLINE | ID: mdl-32200799

RESUMEN

Influenza A virus (IAV) is a lytic RNA virus that triggers receptor-interacting serine/threonine-protein kinase 3 (RIPK3)-mediated pathways of apoptosis and mixed lineage kinase domain-like pseudokinase (MLKL)-dependent necroptosis in infected cells. ZBP1 initiates RIPK3-driven cell death by sensing IAV RNA and activating RIPK3. Here, we show that replicating IAV generates Z-RNAs, which activate ZBP1 in the nucleus of infected cells. ZBP1 then initiates RIPK3-mediated MLKL activation in the nucleus, resulting in nuclear envelope disruption, leakage of DNA into the cytosol, and eventual necroptosis. Cell death induced by nuclear MLKL was a potent activator of neutrophils, a cell type known to drive inflammatory pathology in virulent IAV disease. Consequently, MLKL-deficient mice manifest reduced nuclear disruption of lung epithelia, decreased neutrophil recruitment into infected lungs, and increased survival following a lethal dose of IAV. These results implicate Z-RNA as a new pathogen-associated molecular pattern and describe a ZBP1-initiated nucleus-to-plasma membrane "inside-out" death pathway with potentially pathogenic consequences in severe cases of influenza.


Asunto(s)
Virus de la Influenza A/genética , Necroptosis/genética , Proteínas de Unión al ARN/metabolismo , Animales , Apoptosis/genética , Muerte Celular/genética , Línea Celular Tumoral , Femenino , Virus de la Influenza A/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Necrosis/metabolismo , Fosforilación , Proteínas Quinasas/metabolismo , ARN/metabolismo , ARN Bicatenario/genética , ARN Bicatenario/metabolismo , Proteínas de Unión al ARN/genética , Proteína Serina-Treonina Quinasas de Interacción con Receptores/metabolismo , Proteína Serina-Treonina Quinasas de Interacción con Receptores/fisiología
11.
Cell ; 183(6): 1617-1633.e22, 2020 12 10.
Artículo en Inglés | MEDLINE | ID: mdl-33259802

RESUMEN

Histone H3.3 glycine 34 to arginine/valine (G34R/V) mutations drive deadly gliomas and show exquisite regional and temporal specificity, suggesting a developmental context permissive to their effects. Here we show that 50% of G34R/V tumors (n = 95) bear activating PDGFRA mutations that display strong selection pressure at recurrence. Although considered gliomas, G34R/V tumors actually arise in GSX2/DLX-expressing interneuron progenitors, where G34R/V mutations impair neuronal differentiation. The lineage of origin may facilitate PDGFRA co-option through a chromatin loop connecting PDGFRA to GSX2 regulatory elements, promoting PDGFRA overexpression and mutation. At the single-cell level, G34R/V tumors harbor dual neuronal/astroglial identity and lack oligodendroglial programs, actively repressed by GSX2/DLX-mediated cell fate specification. G34R/V may become dispensable for tumor maintenance, whereas mutant-PDGFRA is potently oncogenic. Collectively, our results open novel research avenues in deadly tumors. G34R/V gliomas are neuronal malignancies where interneuron progenitors are stalled in differentiation by G34R/V mutations and malignant gliogenesis is promoted by co-option of a potentially targetable pathway, PDGFRA signaling.


Asunto(s)
Neoplasias Encefálicas/genética , Carcinogénesis/genética , Glioma/genética , Histonas/genética , Interneuronas/metabolismo , Mutación/genética , Células-Madre Neurales/metabolismo , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/genética , Animales , Astrocitos/metabolismo , Astrocitos/patología , Neoplasias Encefálicas/patología , Carcinogénesis/patología , Linaje de la Célula , Reprogramación Celular/genética , Cromatina/metabolismo , Embrión de Mamíferos/metabolismo , Epigénesis Genética , Regulación Neoplásica de la Expresión Génica , Silenciador del Gen , Glioma/patología , Histonas/metabolismo , Lisina/metabolismo , Ratones Endogámicos C57BL , Modelos Biológicos , Clasificación del Tumor , Oligodendroglía/metabolismo , Regiones Promotoras Genéticas/genética , Prosencéfalo/embriología , Receptor alfa de Factor de Crecimiento Derivado de Plaquetas/metabolismo , Transcripción Genética , Transcriptoma/genética
12.
Nat Immunol ; 23(2): 177-185, 2022 02.
Artículo en Inglés | MEDLINE | ID: mdl-35105983

RESUMEN

Children and adolescents exhibit a broad range of clinical outcomes from SARS-CoV-2 infection, with the majority having minimal to mild symptoms. Additionally, some succumb to a severe hyperinflammatory post-infectious complication called multisystem inflammatory syndrome in children (MIS-C), predominantly affecting previously healthy individuals. Studies characterizing the immunological differences associated with these clinical outcomes have identified pathways important for host immunity to SARS-CoV-2 and innate modulators of disease severity. In this Review, we delineate the immunological mechanisms underlying the spectrum of pediatric immune response to SARS-CoV-2 infection in comparison with that of adults.


Asunto(s)
COVID-19/complicaciones , COVID-19/inmunología , Inmunidad Innata , SARS-CoV-2/inmunología , Síndrome de Respuesta Inflamatoria Sistémica/inmunología , Adolescente , Desarrollo del Adolescente , Factores de Edad , Enfermedades Asintomáticas , COVID-19/diagnóstico , COVID-19/virología , Niño , Desarrollo Infantil , Comorbilidad , Interacciones Huésped-Patógeno , Humanos , Factores de Riesgo , SARS-CoV-2/patogenicidad , Índice de Severidad de la Enfermedad , Síndrome de Respuesta Inflamatoria Sistémica/diagnóstico , Síndrome de Respuesta Inflamatoria Sistémica/virología
13.
Nat Immunol ; 23(5): 781-790, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35383307

RESUMEN

Although mRNA vaccine efficacy against severe coronavirus disease 2019 remains high, variant emergence has prompted booster immunizations. However, the effects of repeated exposures to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigens on memory T cells are poorly understood. Here, we utilize major histocompatibility complex multimers with single-cell RNA sequencing to profile SARS-CoV-2-responsive T cells ex vivo from humans with one, two or three antigen exposures, including vaccination, primary infection and breakthrough infection. Exposure order determined the distribution between spike-specific and non-spike-specific responses, with vaccination after infection leading to expansion of spike-specific T cells and differentiation to CCR7-CD45RA+ effectors. In contrast, individuals after breakthrough infection mount vigorous non-spike-specific responses. Analysis of over 4,000 epitope-specific T cell antigen receptor (TCR) sequences demonstrates that all exposures elicit diverse repertoires characterized by shared TCR motifs, confirmed by monoclonal TCR characterization, with no evidence for repertoire narrowing from repeated exposure. Our findings suggest that breakthrough infections diversify the T cell memory repertoire and current vaccination protocols continue to expand and differentiate spike-specific memory.


Asunto(s)
COVID-19 , SARS-CoV-2 , Linfocitos T CD8-positivos , Humanos , Fenotipo , Receptores de Antígenos de Linfocitos T/genética , Glicoproteína de la Espiga del Coronavirus/genética , Vacunas Sintéticas , Vacunas de ARNm
14.
Cell ; 176(3): 435-447.e15, 2019 01 24.
Artículo en Inglés | MEDLINE | ID: mdl-30611538

RESUMEN

Mitochondrial ADP/ATP carriers transport ADP into the mitochondrial matrix for ATP synthesis, and ATP out to fuel the cell, by cycling between cytoplasmic-open and matrix-open states. The structure of the cytoplasmic-open state is known, but it has proved difficult to understand the transport mechanism in the absence of a structure in the matrix-open state. Here, we describe the structure of the matrix-open state locked by bongkrekic acid bound in the ADP/ATP-binding site at the bottom of the central cavity. The cytoplasmic side of the carrier is closed by conserved hydrophobic residues, and a salt bridge network, braced by tyrosines. Glycine and small amino acid residues allow close-packing of helices on the matrix side. Uniquely, the carrier switches between states by rotation of its three domains about a fulcrum provided by the substrate-binding site. Because these features are highly conserved, this mechanism is likely to apply to the whole mitochondrial carrier family. VIDEO ABSTRACT.


Asunto(s)
Mitocondrias/metabolismo , Translocasas Mitocondriales de ADP y ATP/metabolismo , Translocasas Mitocondriales de ADP y ATP/ultraestructura , Adenosina Difosfato/metabolismo , Adenosina Trifosfato/metabolismo , Secuencia de Aminoácidos , Sitios de Unión , Transporte Biológico , Ácido Bongcréquico/metabolismo , Citoplasma/metabolismo , Mitocondrias/fisiología , Translocasas Mitocondriales de ADP y ATP/fisiología , Proteínas de Transporte de Membrana Mitocondrial/metabolismo , Proteínas de Transporte de Membrana Mitocondrial/fisiología , Proteínas de Transporte de Membrana Mitocondrial/ultraestructura , Modelos Moleculares , Conformación Proteica , Estructura Secundaria de Proteína , Saccharomyces cerevisiae/metabolismo , Proteínas de Saccharomyces cerevisiae/metabolismo
15.
Immunity ; 56(5): 1098-1114.e10, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37003256

RESUMEN

Poor maternal diet during pregnancy is a risk factor for severe lower respiratory infections (sLRIs) in the offspring, but the underlying mechanisms remain elusive. Here, we demonstrate that in mice a maternal low-fiber diet (LFD) led to enhanced LRI severity in infants because of delayed plasmacytoid dendritic cell (pDC) recruitment and perturbation of regulatory T cell expansion in the lungs. LFD altered the composition of the maternal milk microbiome and assembling infant gut microbiome. These microbial changes reduced the secretion of the DC growth factor Flt3L by neonatal intestinal epithelial cells and impaired downstream pDC hematopoiesis. Therapy with a propionate-producing bacteria isolated from the milk of high-fiber diet-fed mothers, or supplementation with propionate, conferred protection against sLRI by restoring gut Flt3L expression and pDC hematopoiesis. Our findings identify a microbiome-dependent Flt3L axis in the gut that promotes pDC hematopoiesis in early life and confers disease resistance against sLRIs.


Asunto(s)
Microbiota , Infecciones del Sistema Respiratorio , Animales , Femenino , Ratones , Embarazo , Células Dendríticas , Dieta , Propionatos
16.
Immunity ; 56(4): 879-892.e4, 2023 04 11.
Artículo en Inglés | MEDLINE | ID: mdl-36958334

RESUMEN

Although the protective role of neutralizing antibodies against COVID-19 is well established, questions remain about the relative importance of cellular immunity. Using 6 pMHC multimers in a cohort with early and frequent sampling, we define the phenotype and kinetics of recalled and primary T cell responses following Delta or Omicron breakthrough infection in previously vaccinated individuals. Recall of spike-specific CD4+ T cells was rapid, with cellular proliferation and extensive activation evident as early as 1 day post symptom onset. Similarly, spike-specific CD8+ T cells were rapidly activated but showed variable degrees of expansion. The frequency of activated SARS-CoV-2-specific CD8+ T cells at baseline and peak inversely correlated with peak SARS-CoV-2 RNA levels in nasal swabs and accelerated viral clearance. Our study demonstrates that a rapid and extensive recall of memory T cell populations occurs early after breakthrough infection and suggests that CD8+ T cells contribute to the control of viral replication in breakthrough SARS-CoV-2 infections.


Asunto(s)
COVID-19 , Humanos , SARS-CoV-2 , Linfocitos T CD8-positivos , Infección Irruptiva , ARN Viral , Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunación
17.
Cell ; 170(1): 142-157.e19, 2017 Jun 29.
Artículo en Inglés | MEDLINE | ID: mdl-28648661

RESUMEN

Immune-checkpoint-blockade (ICB)-mediated rejuvenation of exhausted T cells has emerged as a promising approach for treating various cancers and chronic infections. However, T cells that become fully exhausted during prolonged antigen exposure remain refractory to ICB-mediated rejuvenation. We report that blocking de novo DNA methylation in activated CD8 T cells allows them to retain their effector functions despite chronic stimulation during a persistent viral infection. Whole-genome bisulfite sequencing of antigen-specific murine CD8 T cells at the effector and exhaustion stages of an immune response identified progressively acquired heritable de novo methylation programs that restrict T cell expansion and clonal diversity during PD-1 blockade treatment. Moreover, these exhaustion-associated DNA-methylation programs were acquired in tumor-infiltrating PD-1hi CD8 T cells, and approaches to reverse these programs improved T cell responses and tumor control during ICB. These data establish de novo DNA-methylation programming as a regulator of T cell exhaustion and barrier of ICB-mediated T cell rejuvenation.


Asunto(s)
Linfocitos T CD8-positivos/citología , Epigénesis Genética , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Adenocarcinoma/tratamiento farmacológico , Animales , Linfocitos T CD8-positivos/inmunología , Metilación de ADN , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Trasplante de Neoplasias , Neoplasias de la Próstata/tratamiento farmacológico , Virosis/tratamiento farmacológico
18.
Nat Immunol ; 20(5): 613-625, 2019 05.
Artículo en Inglés | MEDLINE | ID: mdl-30778243

RESUMEN

Influenza A, B and C viruses (IAV, IBV and ICV, respectively) circulate globally and infect humans, with IAV and IBV causing the most severe disease. CD8+ T cells confer cross-protection against IAV strains, however the responses of CD8+ T cells to IBV and ICV are understudied. We investigated the breadth of CD8+ T cell cross-recognition and provide evidence of CD8+ T cell cross-reactivity across IAV, IBV and ICV. We identified immunodominant CD8+ T cell epitopes from IBVs that were protective in mice and found memory CD8+ T cells directed against universal and influenza-virus-type-specific epitopes in the blood and lungs of healthy humans. Lung-derived CD8+ T cells displayed tissue-resident memory phenotypes. Notably, CD38+Ki67+CD8+ effector T cells directed against novel epitopes were readily detected in IAV- or IBV-infected pediatric and adult subjects. Our study introduces a new paradigm whereby CD8+ T cells confer unprecedented cross-reactivity across all influenza viruses, a key finding for the design of universal vaccines.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Reacciones Cruzadas/inmunología , Gammainfluenzavirus/inmunología , Virus de la Influenza A/inmunología , Virus de la Influenza B/inmunología , Gripe Humana/inmunología , Adolescente , Adulto , Anciano , Animales , Linfocitos T CD8-positivos/virología , Niño , Epítopos de Linfocito T/inmunología , Femenino , Humanos , Virus de la Influenza A/fisiología , Virus de la Influenza B/fisiología , Vacunas contra la Influenza/inmunología , Gripe Humana/virología , Gammainfluenzavirus/fisiología , Masculino , Ratones , Persona de Mediana Edad , Adulto Joven
19.
Immunity ; 55(5): 749-780, 2022 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-35545027

RESUMEN

The lungs are constantly exposed to inhaled debris, allergens, pollutants, commensal or pathogenic microorganisms, and respiratory viruses. As a result, innate and adaptive immune responses in the respiratory tract are tightly regulated and are in continual flux between states of enhanced pathogen clearance, immune-modulation, and tissue repair. New single-cell-sequencing techniques are expanding our knowledge of airway cellular complexity and the nuanced connections between structural and immune cell compartments. Understanding these varied interactions is critical in treatment of human pulmonary disease and infections and in next-generation vaccine design. Here, we review the innate and adaptive immune responses in the lung and airways following infection and vaccination, with particular focus on influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The ongoing SARS-CoV-2 pandemic has put pulmonary research firmly into the global spotlight, challenging previously held notions of respiratory immunity and helping identify new populations at high risk for respiratory distress.


Asunto(s)
COVID-19 , SARS-CoV-2 , COVID-19/prevención & control , Humanos , Inmunidad Innata , Inmunidad Mucosa , Pulmón , Vacunación
20.
Immunity ; 55(4): 656-670.e8, 2022 04 12.
Artículo en Inglés | MEDLINE | ID: mdl-35366396

RESUMEN

Reinvigoration of exhausted CD8+ T (Tex) cells by checkpoint immunotherapy depends on the activation of precursors of exhausted T (Tpex) cells, but the local anatomical context of their maintenance, differentiation, and interplay with other cells is not well understood. Here, we identified transcriptionally distinct Tpex subpopulations, mapped their differentiation trajectories via transitory cellular states toward Tex cells, and localized these cell states to specific splenic niches. Conventional dendritic cells (cDCs) were critical for successful αPD-L1 therapy and were required to mediate viral control. cDC1s were dispensable for Tpex cell expansion but provided an essential niche to promote Tpex cell maintenance, preventing their overactivation and T-cell-mediated immunopathology. Mechanistically, cDC1s insulated Tpex cells via MHC-I-dependent interactions to prevent their activation within other inflammatory environments that further aggravated their exhaustion. Our findings reveal that cDC1s maintain and safeguard Tpex cells within distinct anatomical niches to balance viral control, exhaustion, and immunopathology.


Asunto(s)
Linfocitos T CD8-positivos , Células Dendríticas , Diferenciación Celular , Inmunoterapia , Recuento de Linfocitos
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