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1.
Annu Rev Immunol ; 38: 229-247, 2020 04 26.
Artículo en Inglés | MEDLINE | ID: mdl-31928469

RESUMEN

Neonatal CD4+ and CD8+ T cells have historically been characterized as immature or defective. However, recent studies prompt a reinterpretation of the functions of neonatal T cells. Rather than a population of cells always falling short of expectations set by their adult counterparts, neonatal T cells are gaining recognition as a distinct population of lymphocytes well suited for the rapidly changing environment in early life. In this review, I will highlight new evidence indicating that neonatal T cells are not inert or less potent versions of adult T cells but instead are a broadly reactive layer of T cells poised to quickly develop into regulatory or effector cells, depending on the needs of the host. In this way, neonatal T cells are well adapted to provide fast-acting immune protection against foreign pathogens, while also sustaining tolerance to self-antigens.


Asunto(s)
Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Inmunidad Adaptativa , Animales , Biomarcadores , Diferenciación Celular/inmunología , Interacciones Huésped-Patógeno , Humanos , Memoria Inmunológica , Activación de Linfocitos/inmunología , Células Progenitoras Linfoides/citología , Células Progenitoras Linfoides/inmunología , Células Progenitoras Linfoides/metabolismo , Fenotipo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Subgrupos de Linfocitos T/citología
2.
Cell ; 174(1): 117-130.e14, 2018 06 28.
Artículo en Inglés | MEDLINE | ID: mdl-29909981

RESUMEN

Heterogeneity is a hallmark feature of the adaptive immune system in vertebrates. Following infection, naive T cells differentiate into various subsets of effector and memory T cells, which help to eliminate pathogens and maintain long-term immunity. The current model suggests there is a single lineage of naive T cells that give rise to different populations of effector and memory T cells depending on the type and amounts of stimulation they encounter during infection. Here, we have discovered that multiple sub-populations of cells exist in the naive CD8+ T cell pool that are distinguished by their developmental origin, unique transcriptional profiles, distinct chromatin landscapes, and different kinetics and phenotypes after microbial challenge. These data demonstrate that the naive CD8+ T cell pool is not as homogeneous as previously thought and offers a new framework for explaining the remarkable heterogeneity in the effector and memory T cell subsets that arise after infection.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Genes del Desarrollo , Listeria monocytogenes/patogenicidad , Animales , Linfocitos T CD8-positivos/efectos de los fármacos , Linfocitos T CD8-positivos/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Cromatina/metabolismo , Citocinas/farmacología , Epítopos de Linfocito T/genética , Epítopos de Linfocito T/metabolismo , Memoria Inmunológica , Interferón gamma/metabolismo , Células Asesinas Naturales/citología , Células Asesinas Naturales/metabolismo , Listeria monocytogenes/metabolismo , Ratones , Ratones Endogámicos C57BL , Análisis de Componente Principal , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Timo/trasplante , Factores de Transcripción/genética , Factores de Transcripción/metabolismo , Transcriptoma
3.
Immunol Rev ; 315(1): 108-125, 2023 05.
Artículo en Inglés | MEDLINE | ID: mdl-36653953

RESUMEN

Historically, the immune system was believed to develop along a linear axis of maturity from fetal life to adulthood. Now, it is clear that distinct layers of immune cells are generated from unique waves of hematopoietic progenitors during different windows of development. This model, known as the layered immune model, has provided a useful framework for understanding why distinct lineages of B cells and γδ T cells arise in succession and display unique functions in adulthood. However, the layered immune model has not been applied to CD8+ T cells, which are still often viewed as a uniform population of cells belonging to the same lineage, with functional differences between cells arising from environmental factors encountered during infection. Recent studies have challenged this idea, demonstrating that not all CD8+ T cells are created equally and that the functions of individual CD8+ T cells in adults are linked to when they were created in the host. In this review, we discuss the accumulating evidence suggesting there are distinct ontogenetic subpopulations of CD8+ T cells and propose that the layered immune model be extended to the CD8+ T cell compartment.


Asunto(s)
Linfocitos T CD8-positivos , Sistema Inmunológico , Subgrupos de Linfocitos T , Humanos , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Desarrollo Humano/fisiología , Sistema Inmunológico/citología , Sistema Inmunológico/crecimiento & desarrollo , Sistema Inmunológico/inmunología , Sistema Inmunológico/fisiología , Inmunidad/inmunología , Inmunidad/fisiología , Subgrupos de Linfocitos T/inmunología
4.
J Immunol ; 213(7): 933-939, 2024 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-39132993

RESUMEN

The most common congenital viral infection is CMV, which leads to numerous neurologic disabilities. Using a mouse model of congenital CMV, we previously determined that Ag-specific CD8+ T cells traffic to the brain in a CCR9-dependent manner. The mechanism by which these CD8+ T cells acquire a CCR9-dependent "brain-tropic" phenotype remains unclear. In this study, we identify the key factor that imprints brain homing specificity on CD8+ T cells, the source of production, and the location where CCR9 expression is induced. Specifically, we discovered that CCR9 is induced on CD8+ T cells by retinoic acid-producing CD8α+ dendritic cells in the cervical lymph node postinfection. We found that retinoic acid is important for CD8+ T cells to establish tissue residency in the brain. Collectively, our data expand the role of retinoic acid during infection and mechanistically demonstrate how CD8+ T cells are primed to protect the brain during congenital viral infection.


Asunto(s)
Encéfalo , Linfocitos T CD8-positivos , Infecciones por Citomegalovirus , Tretinoina , Animales , Linfocitos T CD8-positivos/inmunología , Tretinoina/metabolismo , Ratones , Infecciones por Citomegalovirus/inmunología , Encéfalo/inmunología , Ratones Endogámicos C57BL , Células Dendríticas/inmunología , Citomegalovirus/inmunología , Modelos Animales de Enfermedad , Movimiento Celular/inmunología
5.
J Immunol ; 212(5): 834-843, 2024 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-38231127

RESUMEN

Chronic viral infections, such as HIV and hepatitis C virus, represent a major public health problem. Although it is well understood that neonates and adults respond differently to chronic viral infections, the underlying mechanisms remain unknown. In this study, we transferred neonatal and adult CD8+ T cells into a mouse model of chronic infection (lymphocytic choriomeningitis virus clone 13) and dissected out the key cell-intrinsic differences that alter their ability to protect the host. Interestingly, we found that neonatal CD8+ T cells preferentially became effector cells early in chronic infection compared with adult CD8+ T cells and expressed higher levels of genes associated with cell migration and effector cell differentiation. During the chronic phase of infection, the neonatal cells retained more immune functionality and expressed lower levels of surface markers and genes related to exhaustion. Because the neonatal cells protect from viral replication early in chronic infection, the altered differentiation trajectories of neonatal and adult CD8+ T cells is functionally significant. Together, our work demonstrates how cell-intrinsic differences between neonatal and adult CD8+ T cells influence key cell fate decisions during chronic infection.


Asunto(s)
Coriomeningitis Linfocítica , Ratones , Animales , Infección Persistente , Virus de la Coriomeningitis Linfocítica , Linfocitos T CD8-positivos , Diferenciación Celular , Ratones Endogámicos C57BL , Enfermedad Crónica
6.
Trends Immunol ; 43(3): 195-209, 2022 03.
Artículo en Inglés | MEDLINE | ID: mdl-35094945

RESUMEN

The fate-mapping mouse has become an essential tool in the immunologist's toolbox. Although traditionally used by developmental biologists to trace the origins of cells, immunologists are turning to fate-mapping to better understand the development and function of immune cells. Thus, an expansion in the variety of fate-mapping mouse models has occurred to answer fundamental questions about the immune system. These models are also being combined with new genetic tools to study cancer, infection, and autoimmunity. In this review, we summarize different types of fate-mapping mice and describe emerging technologies that might allow immunologists to leverage this valuable tool and expand our functional knowledge of the immune system.


Asunto(s)
Tecnología , Animales , Linaje de la Célula , Humanos , Ratones , Ratones Transgénicos
7.
Proc Natl Acad Sci U S A ; 119(49): e2212548119, 2022 12 06.
Artículo en Inglés | MEDLINE | ID: mdl-36442114

RESUMEN

Microbial exposure during development can elicit long-lasting effects on the health of an individual. However, how microbial exposure in early life leads to permanent changes in the immune system is unknown. Here, we show that the microbial environment alters the set point for immune susceptibility by altering the developmental architecture of the CD8+ T cell compartment. In particular, early microbial exposure results in the preferential expansion of highly responsive fetal-derived CD8+ T cells that persist into adulthood and provide the host with enhanced immune protection against intracellular pathogens. Interestingly, microbial education of fetal-derived CD8+ T cells occurs during thymic development rather than in the periphery and involves the acquisition of a more effector-like epigenetic program. Collectively, our results provide a conceptual framework for understanding how microbial colonization in early life leads to lifelong changes in the immune system.


Asunto(s)
Linfocitos T CD8-positivos , Feto , Inmunidad , Diferenciación Celular , Escolaridad , Epigenómica , Feto/inmunología , Feto/microbiología
8.
J Immunol ; 209(12): 2281-2286, 2022 12 15.
Artículo en Inglés | MEDLINE | ID: mdl-36469843

RESUMEN

CD8+ T lymphocytes infiltrate the brain during congenital CMV infection and promote viral clearance. However, the mechanisms by which CD8+ T cells are recruited to the brain remain unclear. Using a mouse model of congenital CMV, we found a gut-homing chemokine receptor (CCR9) was preferentially expressed in CD8+ T cells localized in the brain postinfection. In the absence of CCR9 or CCL25 (CCR9's ligand) expression, CD8+ T cells failed to migrate to key sites of infection in the brain and protect the host from severe forms of disease. Interestingly, we found that expression of CCR9 on CD8+ T cells was also responsible for spatial temporal positioning of T cells in the brain. Collectively, our data demonstrate that the CMV-infected brain uses a similar mechanism for CD8+ T cell homing as the small intestine.


Asunto(s)
Infecciones por Citomegalovirus , Receptores CCR , Humanos , Receptores CCR/metabolismo , Linfocitos T CD8-positivos/metabolismo , Intestino Delgado/metabolismo , Infecciones por Citomegalovirus/metabolismo , Encéfalo/metabolismo
9.
Proc Natl Acad Sci U S A ; 116(10): 3974-3981, 2019 03 05.
Artículo en Inglés | MEDLINE | ID: mdl-30765525

RESUMEN

Accumulating evidence indicates that the immune system does not develop in a linear fashion, but rather as distinct developmental layers formed from sequential waves of hematopoietic stem cells, each giving rise to unique populations of immune cells at different stages of development. Although recent studies have indicated that conventional CD8+ T cells produced in early life persist into adulthood and exhibit distinct roles during infection, the developmental architecture of the peripheral T cell compartment remains undefined. In this study, we used a mouse model to permanently label CD8+ T cells produced during distinct windows of development and traced their history to generate fate maps of CD8+ T cells produced during different stages of life. We then used mathematical modeling to understand the age structure of the CD8+ T cell compartment across the lifespan. Interestingly, we found that survival rate of CD8+ T cells depends on both the age and developmental origin of the cells. Recently produced cells show an initial rapid decay rate, which slows with age of the animal at which the cells were produced. For cells produced at any age, the rate of decay also slows with the age of the cell. We derive a function to describe this and predict the "age distribution" of the CD8+ T cell pool for animals of any given age. These data provide a quantitative framework for understanding the ontogeny of the CD8+ T cell compartment and help to contextualize age-related changes in the CD8+ T cell response to infection.


Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD8-positivos/inmunología , Modelos Inmunológicos , Envejecimiento/genética , Animales , Linfocitos T CD8-positivos/citología , Ratones , Ratones Transgénicos
10.
J Immunol ; 203(10): 2571-2576, 2019 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-31597706

RESUMEN

Neonates often develop poor immunity against intracellular pathogens. Because CD8+ T cells are essential for eliminating infectious agents, it is crucial to understand why they behave differently in early life. Previous studies in mice have demonstrated that neonatal CD8+ T cells fail to form memory because of an intrinsic propensity to differentiate into short-lived effectors. However, the underlying mechanisms remain undefined. We now show that neonatal CD8+ T cells exhibit higher glycolytic activity than adult CD8+ T cells postinfection, which may be due to age-related differences in Lin28b expression. Importantly, when glycolysis is pharmacologically inhibited, the impaired formation of neonatal memory CD8+ T cells can be restored. Collectively, these data suggest that neonatal CD8+ T cells are inherently biased toward undergoing glycolytic metabolism postinfection, which compromises their ability to develop into memory CD8+ T cells in early life.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Glucólisis/inmunología , Memoria Inmunológica/inmunología , Traslado Adoptivo/métodos , Animales , Animales Recién Nacidos , Linfocitos T CD8-positivos/efectos de los fármacos , Células Cultivadas , Desoxiglucosa/farmacología , Glucólisis/efectos de los fármacos , Memoria Inmunológica/efectos de los fármacos , Interleucina-2/farmacología , Listeria monocytogenes/inmunología , Listeriosis/inmunología , Listeriosis/microbiología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo
11.
Blood ; 128(26): 3073-3082, 2016 12 29.
Artículo en Inglés | MEDLINE | ID: mdl-28034872

RESUMEN

During the ontogeny of the mammalian immune system, distinct lineages of cells arise from fetal and adult hematopoietic stem cells (HSCs) during specific stages of development. However, in some cases, the same immune cell type is produced by both HSC populations, resulting in the generation of phenotypically similar cells with distinct origins and divergent functional properties. In this report, we demonstrate that neonatal CD8+ T cells preferentially become short-lived effectors and adult CD8+ T cells selectively form long-lived memory cells after infection because they are derived from distinct progenitor cells. Notably, we find that naïve neonatal CD8+ T cells originate from a progenitor cell that is distinguished by expression of Lin28b. Remarkably, ectopic expression of Lin28b enables adult progenitors to give rise to CD8+ T cells that are phenotypically and functionally analogous to those found in neonates. These findings suggest that neonatal and adult CD8+ T cells belong to separate lineages of CD8+ T cells, and potentially explain why it is challenging to elicit memory CD8+ T cells in early life.


Asunto(s)
Células Madre Adultas/citología , Linfocitos T CD8-positivos/citología , Células Madre Fetales/citología , Feto/citología , Células Madre Adultas/metabolismo , Envejecimiento , Animales , Animales Recién Nacidos , Biomarcadores/metabolismo , Proteínas de Unión al ADN/metabolismo , Células Madre Fetales/metabolismo , Perfilación de la Expresión Génica , Memoria Inmunológica , Ratones Endogámicos C57BL , Fenotipo , Proteínas de Unión al ARN , Timo/citología
12.
J Immunol ; 196(4): 1604-16, 2016 Feb 15.
Artículo en Inglés | MEDLINE | ID: mdl-26764033

RESUMEN

CMV is the most common congenital infection in the United States. The major target of congenital CMV is the brain, with clinical manifestations including mental retardation, vision impairment, and sensorineural hearing loss. Previous reports have shown that CD8(+) T cells are required to control viral replication and significant numbers of CMV-specific CD8(+) T cells persist in the brain even after the initial infection has been cleared. However, the dynamics of CD8(+) T cells in the brain during latency remain largely undefined. In this report, we used TCR sequencing to track the development and maintenance of neonatal clonotypes in the brain and spleen of mice during chronic infection. Given the discontinuous nature of tissue-resident memory CD8(+) T cells, we hypothesized that neonatal TCR clonotypes would be locked in the brain and persist into adulthood. Surprisingly, we found that the Ag-specific T cell repertoire in neonatal-infected mice diversified during persistent infection in both the brain and spleen, while maintaining substantial similarity between the CD8(+) T cell populations in the brain and spleen in both early and late infection. However, despite the diversification of, and potential interchange between, the spleen and brain Ag-specific T cell repertoires, we observed that germline-encoded TCR clonotypes, characteristic of neonatal infection, persisted in the brain, albeit sometimes in low abundance. These results provide valuable insights into the evolution of CD8(+) T cell repertoires following neonatal CMV infection and thus have important implications for the development of therapeutic strategies to control CMV in early life.


Asunto(s)
Encéfalo/inmunología , Linfocitos T CD8-positivos/inmunología , Infecciones por Citomegalovirus/inmunología , Memoria Inmunológica , Animales , Animales Recién Nacidos , Citomegalovirus/inmunología , Genes Codificadores de los Receptores de Linfocitos T , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Bazo/citología , Bazo/inmunología
13.
J Immunol ; 194(1): 210-22, 2015 Jan 01.
Artículo en Inglés | MEDLINE | ID: mdl-25416805

RESUMEN

Beta-catenin signaling has recently been tied to the emergence of tolerogenic dendritic cells (DCs). In this article, we demonstrate a novel role for beta-catenin in directing DC subset development through IFN regulatory factor 8 (IRF8) activation. We found that splenic DC precursors express beta-catenin, and DCs from mice with CD11c-specific constitutive beta-catenin activation upregulated IRF8 through targeting of the Irf8 promoter, leading to in vivo expansion of IRF8-dependent CD8a+, plasmacytoid, and CD103+ CD11b2 DCs. beta-catenin­stabilized CD8a+ DCs secreted elevated IL-12 upon in vitro microbial stimulation, and pharmacological beta-catenin inhibition blocked this response in wild-type cells. Upon infections with Toxoplasma gondii and vaccinia virus, mice with stabilized DC beta-catenin displayed abnormally high Th1 and CD8+ T lymphocyte responses, respectively. Collectively, these results reveal a novel and unexpected function for beta-catenin in programming DC differentiation toward subsets that orchestrate proinflammatory immunity to infection.


Asunto(s)
Células Dendríticas/citología , Células Dendríticas/inmunología , Inflamación/inmunología , Factores Reguladores del Interferón/genética , beta Catenina/inmunología , Animales , Antígenos CD/inmunología , Compuestos Bicíclicos Heterocíclicos con Puentes/farmacología , Antígeno CD11c/inmunología , Antígenos CD8/inmunología , Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Activación Enzimática , Femenino , Cadenas alfa de Integrinas/inmunología , Factores Reguladores del Interferón/inmunología , Interleucina-12/biosíntesis , Interleucina-12/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Carga de Parásitos , Regiones Promotoras Genéticas , Pirimidinonas/farmacología , Receptores de Superficie Celular/genética , Transducción de Señal/inmunología , Bazo/citología , Bazo/inmunología , Células TH1/inmunología , Toxoplasma/inmunología , Toxoplasmosis/inmunología , Vaccinia/inmunología , Virus Vaccinia/inmunología , beta Catenina/antagonistas & inhibidores , beta Catenina/biosíntesis
14.
Immunol Cell Biol ; 94(9): 838-848, 2016 10.
Artículo en Inglés | MEDLINE | ID: mdl-27142943

RESUMEN

Neonates are particularly susceptible to a number of infections, and the neonatal CD8+ T-cell response demonstrates differences in both the phenotype and magnitude of responses to infection compared with adults. However, the underlying basis for these differences is unclear. We have used a mathematical modeling approach to analyze the dynamics of neonatal and adult CD8+ T-cell responses following in vitro stimulation and in vivo infection, which allows us to dissect key cell-intrinsic differences in expansion, differentiation and memory formation. We found that neonatal cells started dividing 8 h earlier and proliferated at a faster rate (0.077 vs 0.105 per day) than adult cells in vitro. In addition, neonatal cells also differentiated more rapidly, as measured by the loss in CD62L and Ly6C expression. We extended our mathematical modeling to analysis of neonatal and adult CD8+ T cells responding in vivo and demonstrated that neonatal cells divide more slowly than adult cells after day 4 post infection. However, neonatal cells differentiate more rapidly, upregulating more KLRG1 per division than adult cells (20% vs 5%). The dynamics of memory formation were also found to be different, with neonatal effector cells showing increased death (1.0 vs 2.45 per day). Comparison of the division of human cord blood and adult naive cells stimulated in vitro showed more division in cord blood-derived cells, consistent with the observations in mice. This work highlights differences of the cell-intrinsic division and differentiation program in neonatal CD8+ T cells.


Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Modelos Inmunológicos , Adolescente , Traslado Adoptivo , Adulto , Animales , Diferenciación Celular , División Celular , Proliferación Celular , Sangre Fetal/citología , Humanos , Memoria Inmunológica , Recién Nacido , Cinética , Masculino , Ratones , Persona de Mediana Edad , Fenotipo , Adulto Joven
15.
J Immunol ; 193(1): 177-84, 2014 Jul 01.
Artículo en Inglés | MEDLINE | ID: mdl-24850719

RESUMEN

Neonates often generate incomplete immunity against intracellular pathogens, although the mechanism of this defect is poorly understood. An important question is whether the impaired development of memory CD8+ T cells in neonates is due to an immature priming environment or lymphocyte-intrinsic defects. In this article, we show that neonatal and adult CD8+ T cells adopted different fates when responding to equal amounts of stimulation in the same host. Whereas adult CD8+ T cells differentiated into a heterogeneous pool of effector and memory cells, neonatal CD8+ T cells preferentially gave rise to short-lived effector cells and exhibited a distinct gene expression profile. Surprisingly, impaired neonatal memory formation was not due to a lack of responsiveness, but instead because neonatal CD8+ T cells expanded more rapidly than adult cells and quickly became terminally differentiated. Collectively, these findings demonstrate that neonatal CD8+ T cells exhibit an imbalance in effector and memory CD8+ T cell differentiation, which impairs the formation of memory CD8+ T cells in early life.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Proliferación Celular , Memoria Inmunológica/fisiología , Animales , Diferenciación Celular/genética , Ratones , Ratones Transgénicos
16.
PLoS Pathog ; 9(9): e1003572, 2013 Sep.
Artículo en Inglés | MEDLINE | ID: mdl-24068921

RESUMEN

Microbial infection during various stages of human development produces widely different clinical outcomes, yet the links between age-related changes in the immune compartment and functional immunity remain unclear. The ability of the immune system to respond to specific antigens and mediate protection in early life is closely correlated with the level of diversification of lymphocyte antigen receptors. We have previously shown that the neonatal primary CD8+ T cell response to replication competent virus is significantly constricted compared to the adult response. In the present study, we have analyzed the subsequent formation of neonatal memory CD8+ T cells and their response to secondary infectious challenge. In particular, we asked whether the less diverse CD8+ T cell clonotypes that are elicited by neonatal vaccination with replication competent virus are 'locked-in' to the adult memory T cell, and thus may compromise the strength of adult immunity. Here we report that neonatal memory CD8+ T cells mediate poor recall responses compared to adults and are comprised of a repertoire of lower avidity T cells. During a later infectious challenge the neonatal memory CD8+ T cells compete poorly with the fully diverse repertoire of naïve adult CD8+ T cells and are outgrown by the adult primary response. This has important implications for the timing of vaccination in early life.


Asunto(s)
Envejecimiento , Linfocitos T CD8-positivos/inmunología , Síndromes de Inmunodeficiencia/etiología , Memoria Inmunológica , Listeriosis/fisiopatología , Modelos Inmunológicos , Vacunas Atenuadas/inmunología , Animales , Animales Recién Nacidos , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , ADN Recombinante/metabolismo , Herpes Simple/inmunología , Herpes Simple/prevención & control , Herpes Simple/virología , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/inmunología , Herpesvirus Humano 1/metabolismo , Sistema Inmunológico/crecimiento & desarrollo , Sistema Inmunológico/inmunología , Sistema Inmunológico/patología , Síndromes de Inmunodeficiencia/inmunología , Síndromes de Inmunodeficiencia/metabolismo , Síndromes de Inmunodeficiencia/patología , Listeria monocytogenes/genética , Listeria monocytogenes/inmunología , Listeria monocytogenes/metabolismo , Listeria monocytogenes/patogenicidad , Listeriosis/inmunología , Listeriosis/microbiología , Listeriosis/prevención & control , Ratones Endogámicos , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Organismos Libres de Patógenos Específicos , Vacunas Atenuadas/efectos adversos , Vaccinia/inmunología , Vaccinia/prevención & control , Vaccinia/virología , Virus Vaccinia/genética , Virus Vaccinia/inmunología , Virus Vaccinia/metabolismo , Virulencia
17.
Proc Natl Acad Sci U S A ; 108(33): 13694-9, 2011 Aug 16.
Artículo en Inglés | MEDLINE | ID: mdl-21813761

RESUMEN

Immunity against new infections declines in the last quartile of life, as do numbers of naive T cells. Peripheral maintenance of naive T cells over the lifespan is necessary because their production drastically declines by puberty, a result of thymic involution. We report that this maintenance is not random in advanced aging. As numbers and diversity of naive CD8(+) T cells declined with aging, surviving cells underwent faster rates of homeostatic proliferation, were selected for high T-cell receptor:pMHC avidity, and preferentially acquired "memory-like" phenotype. These high-avidity precursors preferentially responded to infection and exhibited strong antimicrobial function. Thus, T-cell receptor avidity for self-pMHC provides a proofreading mechanism to maintain some of the fittest T cells in the otherwise crumbling naive repertoire, providing a degree of compensation for numerical and diversity defects in old T cells.


Asunto(s)
Envejecimiento/inmunología , Linfocitos T CD8-positivos/citología , Antígenos HLA/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Proliferación Celular , Senescencia Celular/inmunología , Homeostasis/inmunología , Inmunidad/inmunología , Memoria Inmunológica , Recuento de Linfocitos , Ratones
18.
bioRxiv ; 2024 Jun 17.
Artículo en Inglés | MEDLINE | ID: mdl-38948840

RESUMEN

T cell development is fundamental to immune system establishment, yet how this development changes with age remains poorly understood. Here, we construct a transcriptional and epigenetic atlas of T cell developmental programs in neonatal and adult mice, revealing the ontogeny of divergent gene regulatory programs and their link to age-related differences in phenotype and function. Specifically, we identify a gene module that diverges with age from the earliest stages of genesis and includes programs that govern effector response and cell cycle regulation. Moreover, we reveal that neonates possess more accessible chromatin during early thymocyte development, likely establishing poised gene expression programs that manifest later in thymocyte development. Finally, we leverage this atlas, employing a CRISPR-based perturbation approach coupled with single-cell RNA sequencing as a readout to uncover a conserved transcriptional regulator, Zbtb20, that contributes to age-dependent differences in T cell development. Altogether, our study defines transcriptional and epigenetic programs that regulate age-specific differences in T cell development.

19.
Nat Nanotechnol ; 19(8): 1190-1202, 2024 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-38684809

RESUMEN

Cellular programming of naïve T cells can improve the efficacy of adoptive T-cell therapy. However, the current ex vivo engineering of T cells requires the pre-activation of T cells, which causes them to lose their naïve state. In this study, cationic-polymer-functionalized nanowires were used to pre-program the fate of primary naïve CD8+ T cells to achieve a therapeutic response in vivo. This was done by delivering single or multiple microRNAs to primary naïve mouse and human CD8+ T cells without pre-activation. The use of nanowires further allowed for the delivery of large, whole lentiviral particles with potential for long-term integration. The combination of deletion and overexpression of miR-29 and miR-130 impacted the ex vivo T-cell differentiation fate from the naïve state. The programming of CD8+ T cells using nanowire-delivered co-delivery of microRNAs resulted in the modulation of T-cell fitness by altering the T-cell proliferation, phenotypic and transcriptional regulation, and secretion of effector molecules. Moreover, the in vivo adoptive transfer of murine CD8+ T cells programmed through the nanowire-mediated dual delivery of microRNAs provided enhanced immune protection against different types of intracellular pathogen (influenza and Listeria monocytogenes). In vivo analyses demonstrated that the simultaneous alteration of miR-29 and miR-130 levels in naïve CD8+ T cells reduces the persistence of canonical memory T cells whereas increases the population of short-lived effector T cells. Nanowires could potentially be used to modulate CD8+ T-cell differentiation and achieve a therapeutic response in vivo without the need for pre-activation.


Asunto(s)
Linfocitos T CD8-positivos , MicroARNs , Nanocables , MicroARNs/genética , Animales , Ratones , Supervivencia Celular , Humanos , Expresión Génica , Células Cultivadas , Transcriptoma , Masculino , Femenino , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología
20.
Sci Adv ; 10(1): eadg5461, 2024 Jan 05.
Artículo en Inglés | MEDLINE | ID: mdl-38170764

RESUMEN

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the ongoing global pandemic associated with morbidity and mortality in humans. Although disease severity correlates with immune dysregulation, the cellular mechanisms of inflammation and pathogenesis of COVID-19 remain relatively poorly understood. Here, we used mouse-adapted SARS-CoV-2 strain MA10 to investigate the role of adaptive immune cells in disease. We found that while infected wild-type mice lost ~10% weight by 3 to 4 days postinfection, rag-/- mice lacking B and T lymphocytes did not lose weight. Infected lungs at peak weight loss revealed lower pathology scores, fewer neutrophils, and lower interleukin-6 and tumor necrosis factor-α in rag-/- mice. Mice lacking αß T cells also had less severe weight loss, but adoptive transfer of T and B cells into rag-/- mice did not significantly change the response. Collectively, these findings suggest that while adaptive immune cells are important for clearing SARS-CoV-2 infection, this comes at the expense of increased inflammation and pathology.


Asunto(s)
COVID-19 , SARS-CoV-2 , Humanos , Ratones , Animales , Linfocitos T , Inflamación , Pérdida de Peso , Modelos Animales de Enfermedad
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