Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 23
Filtrar
1.
Cell ; 174(3): 672-687.e27, 2018 07 26.
Artículo en Inglés | MEDLINE | ID: mdl-30053426

RESUMEN

TCR-signaling strength generally correlates with peptide-MHC binding affinity; however, exceptions exist. We find high-affinity, yet non-stimulatory, interactions occur with high frequency in the human T cell repertoire. Here, we studied human TCRs that are refractory to activation by pMHC ligands despite robust binding. Analysis of 3D affinity, 2D dwell time, and crystal structures of stimulatory versus non-stimulatory TCR-pMHC interactions failed to account for their different signaling outcomes. Using yeast pMHC display, we identified peptide agonists of a formerly non-responsive TCR. Single-molecule force measurements demonstrated the emergence of catch bonds in the activating TCR-pMHC interactions, correlating with exclusion of CD45 from the TCR-APC contact site. Molecular dynamics simulations of TCR-pMHC disengagement distinguished agonist from non-agonist ligands based on the acquisition of catch bonds within the TCR-pMHC interface. The isolation of catch bonds as a parameter mediating the coupling of TCR binding and signaling has important implications for TCR and antigen engineering for immunotherapy.


Asunto(s)
Antígenos de Histocompatibilidad Clase I/fisiología , Activación de Linfocitos/fisiología , Adulto , Femenino , Humanos , Cinética , Ligandos , Complejo Mayor de Histocompatibilidad/fisiología , Masculino , Persona de Mediana Edad , Simulación de Dinámica Molecular , Oligopéptidos , Péptidos , Unión Proteica/fisiología , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/fisiología , Transducción de Señal , Imagen Individual de Molécula , Linfocitos T/fisiología
2.
Immunity ; 54(6): 1245-1256.e5, 2021 06 08.
Artículo en Inglés | MEDLINE | ID: mdl-34004140

RESUMEN

We examined how baseline CD4+ T cell repertoire and precursor states impact responses to pathogen infection in humans using primary immunization with yellow fever virus (YFV) vaccine. YFV-specific T cells in unexposed individuals were identified by peptide-MHC tetramer staining and tracked pre- and post-vaccination by tetramers and TCR sequencing. A substantial number of YFV-reactive T cells expressed memory phenotype markers and contained expanded clones in the absence of exposure to YFV. After vaccination, pre-existing YFV-specific T cell populations with low clonal diversity underwent limited expansion, but rare populations with a reservoir of unexpanded TCRs generated robust responses. These altered dynamics reorganized the immunodominance hierarchy and resulted in an overall increase in higher avidity T cells. Thus, instead of further increasing the representation of dominant clones, YFV vaccination recruits rare and more responsive T cells. Our findings illustrate the impact of vaccines in prioritizing T cell responses and reveal repertoire reorganization as a key component of effective vaccination.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Fiebre Amarilla/inmunología , Virus de la Fiebre Amarilla/inmunología , Adulto , Animales , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Antígenos Virales/inmunología , Células Cultivadas , Chlorocebus aethiops , Humanos , Receptores de Antígenos de Linfocitos T/inmunología , Vacunación/métodos , Células Vero , Fiebre Amarilla/virología
3.
Immunity ; 38(2): 373-83, 2013 Feb 21.
Artículo en Inglés | MEDLINE | ID: mdl-23395677

RESUMEN

Although T cell memory is generally thought to require direct antigen exposure, we found an abundance of memory-phenotype cells (20%-90%, averaging over 50%) of CD4(+) T cells specific to viral antigens in adults who had never been infected. These cells express the appropriate memory markers and genes, rapidly produce cytokines, and have clonally expanded. In contrast, the same T cell receptor (TCR) specificities in newborns are almost entirely naïve, which might explain the vulnerability of young children to infections. One mechanism for this phenomenon is TCR cross-reactivity to environmental antigens, and in support of this, we found extensive cross-recognition by HIV-1 and influenza-reactive T lymphocytes to other microbial peptides and expansion of one of these after influenza vaccination. Thus, the presence of these memory-phenotype T cells has significant implications for immunity to novel pathogens, child and adult health, and the influence of pathogen-rich versus hygienic environments.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , Memoria Inmunológica , Gripe Humana/inmunología , Gripe Humana/prevención & control , Adulto , Secuencia de Aminoácidos , Linfocitos T CD4-Positivos/patología , Proliferación Celular , Niño , Células Clonales , Infecciones por VIH/patología , Infecciones por VIH/virología , VIH-1/inmunología , Humanos , Inmunofenotipificación , Recién Nacido , Subtipo H1N1 del Virus de la Influenza A/inmunología , Vacunas contra la Influenza/inmunología , Gripe Humana/patología , Gripe Humana/virología , Datos de Secuencia Molecular , Péptidos/inmunología , Fenotipo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/inmunología , Especificidad del Receptor de Antígeno de Linfocitos T , Vacunación
4.
Immunity ; 39(4): 758-69, 2013 Oct 17.
Artículo en Inglés | MEDLINE | ID: mdl-24035365

RESUMEN

The vast majority of currently licensed human vaccines work on the basis of long-term protective antibody responses. It is now conceivable that an antibody-dependent HIV vaccine might be possible, given the discovery of HIV broadly neutralizing antibodies (bnAbs) in some HIV-infected individuals. However, these antibodies are difficult to develop and have characteristics indicative of a high degree of affinity maturation in germinal centers (GCs). CD4⁺ T follicular helper (Tfh) cells are specialized for B cell help and necessary for GCs. Therefore, the development of HIV bnAbs might depend on Tfh cells. Here, we identified in normal individuals a subpopulation of circulating memory PD-1⁺CXCR5⁺CD4⁺ T cells that are resting memory cells most related to bona fide GC Tfh cells by gene expression profile, cytokine profile, and functional properties. Importantly, the frequency of these cells correlated with the development of bnAbs against HIV in a large cohort of HIV⁺ individuals.


Asunto(s)
Anticuerpos Neutralizantes/biosíntesis , Anticuerpos Anti-VIH/biosíntesis , Infecciones por VIH/inmunología , VIH-1/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Receptores CXCR5/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Secuencia de Aminoácidos , Linfocitos B/inmunología , Linfocitos B/patología , Linfocitos B/virología , Expresión Génica , Perfilación de la Expresión Génica , Centro Germinal/inmunología , Centro Germinal/patología , Centro Germinal/virología , Infecciones por VIH/patología , Infecciones por VIH/virología , Humanos , Inmunidad Humoral , Memoria Inmunológica , Datos de Secuencia Molecular , Receptor de Muerte Celular Programada 1/genética , Receptores CXCR3/genética , Receptores CXCR3/inmunología , Receptores CXCR5/genética , Transducción de Señal , Linfocitos T Colaboradores-Inductores/patología , Linfocitos T Colaboradores-Inductores/virología
5.
Proc Natl Acad Sci U S A ; 113(41): E6192-E6198, 2016 10 11.
Artículo en Inglés | MEDLINE | ID: mdl-27681619

RESUMEN

The T-cell receptor (TCR) is required for maturation and function of regulatory T cells (Tregs), but the ligand specificities of Tregs outside the context of transgenic TCRs are largely unknown. Using peptide-MHC tetramers, we isolated rare specific Foxp3+ cells directly ex vivo from adult peripheral blood and defined their frequency and phenotype. We find that a proportion of circulating Tregs recognize foreign antigens and the frequency of these cells are similar to that of self-reactive Tregs in the absence of cognate infection. In contrast, the frequencies of Tregs that recognize some common microbial antigens are significantly reduced in the blood of most adults. Exposure to peripheral antigens likely has a major influence on the balance between Tregs and conventional T-cell subsets because a larger proportion of flu-specific T cells has a regulatory cell phenotype in the cord blood. Consistent with this finding, we show that lymphocytic choriomeningitis virus infection can directly modulate the ratio of virus-specific effectors and Tregs in mice. The resulting change in the balance within an antigen-specific T-cell population further correlates with the magnitude of effector response and the chronicity of infection. Taken together, our data highlight the importance of antigen specificity in the functional dynamics of the T-cell repertoire. Each specific population of CD4+ T cells in human peripheral blood contains a subset of Tregs at birth, but the balance between regulatory and effector subsets changes in response to peripheral antigen exposure and this could impact the robustness of antipathogen immunity.


Asunto(s)
Antígenos/inmunología , Activación de Linfocitos/inmunología , Subgrupos de Linfocitos T/inmunología , Linfocitos T Reguladores/inmunología , Animales , Antígenos Virales/inmunología , Biomarcadores , Citocinas/metabolismo , Epítopos de Linfocito T/inmunología , Sangre Fetal , Perfilación de la Expresión Génica , Antígeno HLA-DR4/genética , Antígeno HLA-DR4/inmunología , Interacciones Huésped-Patógeno/inmunología , Humanos , Memoria Inmunológica , Recuento de Linfocitos , Ratones , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Reguladores/metabolismo , Transcriptoma
6.
Proc Natl Acad Sci U S A ; 113(13): E1890-7, 2016 Mar 29.
Artículo en Inglés | MEDLINE | ID: mdl-26979955

RESUMEN

Here we report a peptide-MHC (pMHC) dodecamer as a "next generation" technology that is a significantly more sensitive and versatile alternative to pMHC tetramers for the detection, isolation, and phenotypic analysis of antigen-specific T cells. In particular, dodecamers are able to detect two- to fivefold more antigen-specific T cells in both human and murine CD4(+)and CD8(+)αß T-cell compartments compared with the equivalent tetramers. The low-affinity, tetramer-negative, dodecamer-positive T cells showed comparable effector cytokine responses as those of high-affinity, tetramer-positive T cells. Dodecamers are able to detect early stage CD4(+)CD8(+)double-positive thymocytes on which T-cell receptors are 10- to 30-fold less dense than mature T cells. Dodecamers also show utility in the analysis of γδ T cells and in cytometry by time-of-flight applications. This construct has a simple structure with a central scaffold protein linked to four streptavidin molecules, each having three pMHC ligands or other molecules. The dodecamer is straightforward and inexpensive to produce and is compatible with current tetramer technology and commercially available streptavidin conjugates.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunofenotipificación/métodos , Péptidos/metabolismo , Animales , Linfocitos T CD4-Positivos/parasitología , Linfocitos T CD8-positivos/fisiología , Citometría de Flujo/métodos , Humanos , Complejo Mayor de Histocompatibilidad , Ratones Transgénicos , Péptidos/química , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Análisis de la Célula Individual/métodos , Linfocitos T/inmunología , Linfocitos T/metabolismo
7.
Immunol Rev ; 255(1): 95-109, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-23947350

RESUMEN

αß T cells are an integral part of protective immunity against pathogens. After precursor cells arise in the adult bone marrow or fetal liver, they migrate to the thymus where they rearrange their T-cell receptor genes (TCR) and undergo selection on the basis of their interactions with ligands expressed by thymic stroma and other cells. Those that survive then exit the thymus to populate the peripheral immune compartment, where they patrol the blood and lymphoid systems. The composition of this pre-immune peripheral repertoire is critically important in determining the robustness of an immune response. In both mice and humans, the magnitude and diversity of a response are directly correlated with the frequency of precursor T cells. Equally relevant are the functional characteristics of these lymphocytes. Engagement of a specific antigen to the TCR activates signaling pathways in the naive T cell that result in cellular proliferation and the acquisition of particular effector functions. A portion of these persist following the resolution of infection and become memory cells. These memory cells can mount a faster and stronger response when they encounter the same antigen at a later time. As the molecular basis for TCR ligand interaction has become better defined, it is clear that some T cells can recognize multiple distinct ligands and therefore T-cell memory developed by exposure to one ligand may play a significant role in the response to a different antigen. Thus, there is an increasing focus on understanding how exposure to related or unrelated antigens influences the T-cell repertoire and impacts subsequent immunity. In this review, we discuss the issue of TCR cross-reactivity in the development of memory phenotype CD4(+) T cells and the implications for pathogen-specific responses. We review both the human and mouse data and discuss the therapeutic implications of these findings in the contexts of infection and vaccination.


Asunto(s)
Memoria Inmunológica , Subgrupos de Linfocitos T/inmunología , Virosis/inmunología , Virus/inmunología , Adulto , Animales , Antígenos Virales/inmunología , Humanos , Receptores de Antígenos de Linfocitos T/metabolismo , Especificidad del Receptor de Antígeno de Linfocitos T/inmunología , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismo , Virosis/metabolismo
8.
Proc Natl Acad Sci U S A ; 109(22): 8676-81, 2012 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-22589303

RESUMEN

Human leukocyte antigen (HLA) genes are the most polymorphic in the human genome. They play a pivotal role in the immune response and have been implicated in numerous human pathologies, especially autoimmunity and infectious diseases. Despite their importance, however, they are rarely characterized comprehensively because of the prohibitive cost of standard technologies and the technical challenges of accurately discriminating between these highly related genes and their many allelles. Here we demonstrate a high-resolution, and cost-effective methodology to type HLA genes by sequencing, which combines the advantage of long-range amplification, the power of high-throughput sequencing platforms, and a unique genotyping algorithm. We calibrated our method for HLA-A, -B, -C, and -DRB1 genes with both reference cell lines and clinical samples and identified several previously undescribed alleles with mismatches, insertions, and deletions. We have further demonstrated the utility of this method in a clinical setting by typing five clinical samples in an Illumina MiSeq instrument with a 5-d turnaround. Overall, this technology has the capacity to deliver low-cost, high-throughput, and accurate HLA typing by multiplexing thousands of samples in a single sequencing run, which will enable comprehensive disease-association studies with large cohorts. Furthermore, this approach can also be extended to include other polymorphic genes.


Asunto(s)
Técnicas de Genotipaje/métodos , Antígenos HLA/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Alelos , Secuencia de Bases , Línea Celular , Cartilla de ADN/genética , Genotipo , Antígenos HLA-A/genética , Antígenos HLA-B/genética , Antígenos HLA-C/genética , Cadenas HLA-DRB1/genética , Humanos , Datos de Secuencia Molecular , Reacción en Cadena de la Polimerasa/métodos , Polimorfismo Genético , Reproducibilidad de los Resultados , Homología de Secuencia de Ácido Nucleico
9.
JCI Insight ; 9(14)2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38861490

RESUMEN

Memory T cells are conventionally associated with durable recall responses. In our longitudinal analyses of CD4+ T cell responses to the yellow fever virus (YFV) vaccine by peptide-MHC tetramers, we unexpectedly found CD45RO-CCR7+ virus-specific CD4+ T cells that expanded shortly after vaccination and persisted months to years after immunization. Further phenotypic analyses revealed the presence of stem cell-like memory T cells within this subset. In addition, after vaccination T cells lacking known memory markers and functionally resembling genuine naive T cells were identified, referred to herein as marker-negative T (TMN) cells. Single-cell TCR sequencing detected expanded clonotypes within the TMN subset and identified TMN TCRs shared with memory and effector T cells. Longitudinal tracking of YFV-specific responses over subsequent years revealed superior stability of TMN cells, which correlated with the longevity of the overall tetramer+ population. These findings uncover additional complexity within the post-immune T cell compartment and implicate TMN cells in durable immune responses.


Asunto(s)
Linfocitos T CD4-Positivos , Células T de Memoria , Vacunación , Vacuna contra la Fiebre Amarilla , Humanos , Linfocitos T CD4-Positivos/inmunología , Vacuna contra la Fiebre Amarilla/inmunología , Células T de Memoria/inmunología , Virus de la Fiebre Amarilla/inmunología , Masculino , Femenino , Memoria Inmunológica/inmunología , Fiebre Amarilla/inmunología , Fiebre Amarilla/prevención & control , Adulto , Estudios Longitudinales , Fenotipo
10.
Immunohorizons ; 7(7): 543-553, 2023 07 01.
Artículo en Inglés | MEDLINE | ID: mdl-37436166

RESUMEN

Immunological experiences lead to the development of specific T and B cell memory, which readies the host for a later pathogen rechallenge. Currently, immunological memory is best understood as a linear process whereby memory responses are generated by and directed against the same pathogen. However, numerous studies have identified memory cells that target pathogens in unexposed individuals. How "pre-existing memory" forms and impacts the outcome of infection remains unclear. In this review, we discuss differences in the composition of baseline T cell repertoire in mice and humans, factors that influence pre-existing immune states, and recent literature on their functional significance. We summarize current knowledge on the roles of pre-existing T cells in homeostasis and perturbation and their impacts on health and disease.


Asunto(s)
Memoria Inmunológica , Linfocitos T , Animales , Humanos , Ratones , Linfocitos T/inmunología
11.
Methods Mol Biol ; 2574: 31-40, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-36087197

RESUMEN

The development of peptide-major histocompatibility complex tetramers has enabled direct characterization and enumeration of antigen-specific T cells. However, the weaker interaction between class II tetramers and CD4+ T cells increases the challenge of using tetramers to analyze CD4+ T cell responses. Here, we provide an optimized class II tetramer staining protocol with a magnetic-bead enrichment strategy for the detection and functional analyses of human antigen-specific CD4+ T cells. This approach enables direct sampling of lymphocytes that recognize specific peptide-MHC complexes, including rare pathogen-specific CD4+ T cells from unexposed individuals.


Asunto(s)
Linfocitos T CD4-Positivos , Antígenos de Histocompatibilidad Clase II , Antígenos , Antígenos de Histocompatibilidad Clase II/análisis , Humanos , Péptidos , Coloración y Etiquetado
12.
Sci Immunol ; 7(76): eabn3127, 2022 10 21.
Artículo en Inglés | MEDLINE | ID: mdl-35857619

RESUMEN

The baseline composition of T cells directly affects later response to pathogens, but the complexity of precursor states remains poorly defined. Here, we examined the baseline state of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific T cells in unexposed individuals. SARS-CoV-2-specific CD4+ T cells were identified in prepandemic blood samples by major histocompatibility complex (MHC) class II tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2-specific T cells that expressed memory phenotype markers. Integrated phenotypic analyses demonstrated diverse preexisting memory states that included cells with distinct polarization features and trafficking potential to barrier tissues. T cell clones generated from tetramer-labeled cells cross-reacted with antigens from commensal bacteria in the skin and gastrointestinal tract. Direct ex vivo tetramer staining for one spike-specific population showed a similar level of cross-reactivity to sequences from endemic coronavirus and commensal bacteria. These data highlight the complexity of precursor T cell repertoire and implicate noninfectious exposures to common microbes as a key factor that shapes human preexisting immunity to SARS-CoV-2.


Asunto(s)
COVID-19 , SARS-CoV-2 , Adulto , Humanos , Memoria Inmunológica , Glicoproteína de la Espiga del Coronavirus , Linfocitos T
13.
Front Immunol ; 13: 859070, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35619703

RESUMEN

Follicular-helper T cells (TFH) are an essential arm of the adaptive immune system. Although TFH were first discovered through their ability to contribute to antibody affinity maturation through co-stimulatory interactions with B cells, new light has been shed on their ability to remain a complex and functionally plastic cell type. Due to a lack sample availability, however, many studies have been limited to characterizing TFH in mice or non-canonical tissue types, such as peripheral blood. Such constraints have resulted in a limited, and sometimes contradictory, understanding of this fundamental cell type. One subset of TFH receiving attention in chronic infection are CXCR3-expressing TFH cells (CXCR3+TFH) due to their abnormal accumulation in secondary lymphoid tissues. Their function and clonal relationship with other TFH subsets in lymphoid tissues during infection, however, remains largely unclear. We thus systematically investigated this and other subsets of TFH within untreated HIV-infected human lymph nodes using Mass CyTOF and a combination of RNA and TCR repertoire sequencing. We show an inflation of the CXCR3+TFH compartment during HIV infection that correlates with a lower HIV burden. Deeper analysis into this population revealed a functional shift of CXCR3+TFH away from germinal center TFH (GC-TFH), including the altered expression of several important transcription factors and cytokines. CXCR3+TFH also upregulated cell migration transcriptional programs and were clonally related to peripheral TFH populations. In combination, these data suggest that CXCR3+TFH have a greater tendency to enter circulation than their CXCR3- counterparts, potentially functioning through distinct modalities that may lead to enhanced defense.


Asunto(s)
Infecciones por VIH , Células T Auxiliares Foliculares , Animales , Centro Germinal , Humanos , Ratones , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores CXCR3/genética , Receptores CXCR3/metabolismo , Linfocitos T Colaboradores-Inductores , Transcriptoma
14.
bioRxiv ; 2021 Nov 30.
Artículo en Inglés | MEDLINE | ID: mdl-34873598

RESUMEN

The baseline composition of T cells directly impacts later response to a pathogen, but the complexity of precursor states remains poorly defined. Here we examined the baseline state of SARS-CoV-2 specific T cells in unexposed individuals. SARS-CoV-2 specific CD4 + T cells were identified in pre-pandemic blood samples by class II peptide-MHC tetramer staining and enrichment. Our data revealed a substantial number of SARS-CoV-2 specific T cells that expressed memory phenotype markers, including memory cells with gut homing receptors. T cell clones generated from tetramer-labeled cells cross-reacted with bacterial peptides and responded to stool lysates in a MHC-dependent manner. Integrated phenotypic analyses revealed additional precursor diversity that included T cells with distinct polarized states and trafficking potential to other barrier tissues. Our findings illustrate a complex pre-existing memory pool poised for immunologic challenges and implicate non-infectious stimuli from commensal colonization as a factor that shapes pre-existing immunity. ONE SENTENCE SUMMARY: Pre-existing immunity to SARS-CoV-2 contains a complex pool of precursor lymphocytes that include differentiated cells with broad tissue tropism and the potential to cross-react with commensal antigens.

15.
Immunohorizons ; 4(12): 774-788, 2020 12 11.
Artículo en Inglés | MEDLINE | ID: mdl-33310880

RESUMEN

The antiviral response to influenza virus is complex and multifaceted, involving many immune cell subsets. There is an urgent need to understand the role of CD4+ T cells, which orchestrate an effective antiviral response, to improve vaccine design strategies. In this study, we analyzed PBMCs from human participants immunized with influenza vaccine, using high-dimensional single-cell proteomic immune profiling by mass cytometry. Data were analyzed using a novel clustering algorithm, denoised ragged pruning, to define possible influenza virus-specific clusters of CD4+ T cells. Denoised ragged pruning identified six clusters of cells. Among these, one cluster (Cluster 3) was found to increase in abundance following stimulation with influenza virus peptide ex vivo. A separate cluster (Cluster 4) was found to expand in abundance between days 0 and 7 postvaccination, indicating that it is vaccine responsive. We examined the expression profiles of all six clusters to characterize their lineage, functionality, and possible role in the response to influenza vaccine. Clusters 3 and 4 consisted of effector memory cells, with high CD154 expression. Cluster 3 expressed cytokines like IL-2, IFN-γ, and TNF-α, whereas Cluster 4 expressed IL-17. Interestingly, some participants had low abundance of Clusters 3 and 4, whereas others had higher abundance of one of these clusters compared with the other. Taken together, we present an approach for identifying novel influenza virus-reactive CD4+ T cell subsets, a method that could help advance understanding of the immune response to influenza, predict responsiveness to vaccines, and aid in better vaccine design.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Vacunas contra la Influenza/inmunología , Gripe Humana/prevención & control , Subgrupos de Linfocitos T/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antígenos CD/análisis , Niño , Análisis por Conglomerados , Citocinas/metabolismo , Femenino , Citometría de Flujo , Humanos , Vacunas contra la Influenza/administración & dosificación , Gripe Humana/inmunología , Masculino , Persona de Mediana Edad , Adulto Joven
16.
Cell Rep ; 28(12): 3047-3060.e7, 2019 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-31533030

RESUMEN

CXCR5 is a key marker of follicular helper T (TFH) cells. Using primary lymph nodes (LNs) from HIV-infected patients, we identified a population of CXCR5- CD4+ T cells with TFH-cell-like features. This CXCR5- subset becomes expanded in severe HIV infection and is characterized by the upregulation of activation markers and high PD-1 and ICOS surface expression. Integrated analyses on the phenotypic heterogeneity, functional capacity, T cell receptor (TCR) repertoire, transcriptional profile, and epigenetic state of CXCR5-PD-1+ICOS+ T cells revealed a shared clonal relationship with TFH cells. CXCR5-PD-1+ICOS+ T cells retained a poised state for CXCR5 expression and exhibited a migratory transcriptional program. TCR sequence overlap revealed a contribution of LN-derived CXCR5-PD-1+ICOS+ T cells to circulating CXCR5- CD4+ T cells with B cell help function. These data link LN pathology to circulating T cells and expand the current understanding on the diversity of T cells that regulate B cell responses during chronic inflammation.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Ganglios Linfáticos/inmunología , Receptores CXCR5/inmunología , Linfocitos B/inmunología , Linfocitos B/patología , Linfocitos T CD4-Positivos/patología , Femenino , Infecciones por VIH/patología , Humanos , Ganglios Linfáticos/patología , Masculino
17.
Isr Med Assoc J ; 10(4): 307-9, 2008 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-18548988

RESUMEN

The completion of the human genome mapping project has provided the necessary backdrop for the development of high-throughput array technologies. In contrast to the reductionist approach to studying the role of a particular molecule in a specific pathway, these technologies enable us to conduct a comprehensive survey of various molecular profiles across different cell types and individuals, placing us one step closer to understanding integrative regulatory networks and the workings of the cell as a whole.


Asunto(s)
Artritis Reumatoide/genética , Análisis de Secuencia por Matrices de Oligonucleótidos/tendencias , Artritis Reumatoide/inmunología , Humanos , Proteómica
18.
Sci Immunol ; 3(22)2018 04 06.
Artículo en Inglés | MEDLINE | ID: mdl-29626170

RESUMEN

Follicular helper CD4+ T cells (TFH) play an integral role in promoting B cell differentiation and affinity maturation. Whereas TFH cell frequencies are increased in lymph nodes (LNs) from individuals infected with HIV, humoral immunity remains impaired during chronic HIV infection. Whether HIV inhibits TFH responses in LNs remains unclear. Advances in this area have been limited by the difficulty of accessing human lymphoid tissues. Here, we combined high-dimensional mass cytometry with T cell receptor repertoire sequencing to interrogate the composition of TFH cells in primary human LNs. We found evidence for intact antigen-driven clonal expansion of TFH cells and selective utilization of specific complementarity-determining region 3 (CDR3) motifs during chronic HIV infection, but the resulting TFH cells acquired an activation-related TFH cell signature characterized by interleukin-21 (IL-21) dominance. These IL-21+ TFH cells contained an oligoclonal HIV-reactive population that preferentially accumulated in patients with severe HIV infection and was associated with aberrant B cell distribution in the same LN. These data indicate that TFH cells remain capable of responding to HIV antigens during chronic HIV infection but become functionally skewed and oligoclonally restricted under persistent antigen stimulation.


Asunto(s)
Infecciones por VIH/inmunología , Ganglios Linfáticos/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Adolescente , Adulto , Secuencia de Aminoácidos , Animales , Linfocitos B/inmunología , Femenino , Humanos , Interleucinas/inmunología , Interleucinas/metabolismo , Activación de Linfocitos/inmunología , Masculino , Persona de Mediana Edad , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Adulto Joven
19.
Sci Immunol ; 3(24)2018 06 01.
Artículo en Inglés | MEDLINE | ID: mdl-29858286

RESUMEN

Current paradigms of CD8+ T cell-mediated protection in HIV infection center almost exclusively on studies of peripheral blood, which is thought to provide a window into immune activity at the predominant sites of viral replication in lymphoid tissues (LTs). Through extensive comparison of blood, thoracic duct lymph (TDL), and LTs in different species, we show that many LT memory CD8+ T cells bear phenotypic, transcriptional, and epigenetic signatures of resident memory T cells (TRMs). Unlike their circulating counterparts in blood or TDL, most of the total and follicular HIV-specific CD8+ T cells in LTs also resemble TRMs Moreover, high frequencies of HIV-specific CD8+ TRMs with skewed clonotypic profiles relative to matched blood samples are present in LTs of individuals who spontaneously control HIV replication in the absence of antiretroviral therapy (elite controllers). Single-cell RNA sequencing analysis confirmed that HIV-specific TRMs are enriched for effector-related immune genes and signatures compared with HIV-specific non-TRMs in elite controllers. Together, these data indicate that previous studies in blood have largely failed to capture the major component of HIV-specific CD8+ T cell responses resident within LTs.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Infecciones por VIH/inmunología , VIH-1/inmunología , Memoria Inmunológica , Tejido Linfoide/citología , Adulto , Animales , Antirreumáticos/farmacología , Antirreumáticos/uso terapéutico , Linfocitos T CD8-positivos/metabolismo , Femenino , Infecciones por VIH/sangre , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , Humanos , Tejido Linfoide/efectos de los fármacos , Tejido Linfoide/inmunología , Macaca mulatta , Masculino , Ratones , Ratones Endogámicos C57BL , Persona de Mediana Edad , Análisis de Secuencia de ARN , Análisis de la Célula Individual/métodos , Carga Viral/efectos de los fármacos , Carga Viral/inmunología , Replicación Viral/efectos de los fármacos , Replicación Viral/inmunología , Adulto Joven
20.
Sci Immunol ; 2(8)2017 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-28620653

RESUMEN

T follicular helper (Tfh) CD4 cells are crucial providers of B cell help during adaptive immune responses. A circulating population of CD4 T cells, termed cTfh, have similarity to lymphoid Tfh, can provide B cell help, and responded to influenza vaccination. However, it is unclear whether human vaccination-induced cTfh respond in an antigen-specific manner and whether they form long-lasting memory. Here, we identified a cTfh population that expressed multiple T cell activation markers and could be readily identified by coexpression of ICOS and CD38. This subset expressed more Bcl-6, c-Maf, and IL-21 than other blood CD4 subsets. Influenza vaccination induced a strong response in the ICOS+CD38+ cTfh at day 7, and this population included hemagglutinin-specific cells by tetramer staining and antigen-stimulated Activation Induced Marker (AIM) expression. Moreover, TCRB sequencing identified a clonal response in ICOS+CD38+ cTfh that correlated strongly with the increased circulating ICOS+CD38+ cTfh frequency and the circulating plasmablast response. In subjects who received successive annual vaccinations, a recurrent oligoclonal response was identified in the ICOS+CD38+ cTfh subset at 7 days after every vaccination. These oligoclonal responses in ICOS+CD38+ cTfh after vaccination persisted in the ICOS-CD38- cTfh repertoire in subsequent years, suggesting clonal maintenance in a memory reservoir in the more-stable ICOS-CD38- cTfh subset. These data highlight the antigen-specificity, lineage relationships and memory properties of human cTfh responses to vaccination, providing new avenues for tracking and monitoring cTfh responses during infection and vaccination in humans.

SELECCIÓN DE REFERENCIAS
DETALLE DE LA BÚSQUEDA