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1.
Nat Immunol ; 24(3): 501-515, 2023 03.
Artículo en Inglés | MEDLINE | ID: mdl-36797499

RESUMEN

Blocking pyrimidine de novo synthesis by inhibiting dihydroorotate dehydrogenase is used to treat autoimmunity and prevent expansion of rapidly dividing cell populations including activated T cells. Here we show memory T cell precursors are resistant to pyrimidine starvation. Although the treatment effectively blocked effector T cells, the number, function and transcriptional profile of memory T cells and their precursors were unaffected. This effect occurred in a narrow time window in the early T cell expansion phase when developing effector, but not memory precursor, T cells are vulnerable to pyrimidine starvation. This vulnerability stems from a higher proliferative rate of early effector T cells as well as lower pyrimidine synthesis capacity when compared with memory precursors. This differential sensitivity is a drug-targetable checkpoint that efficiently diminishes effector T cells without affecting the memory compartment. This cell fate checkpoint might therefore lead to new methods to safely manipulate effector T cell responses.


Asunto(s)
Pirimidinas , Ciclo Celular , Diferenciación Celular
2.
Nature ; 571(7764): 265-269, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31207605

RESUMEN

Cytotoxic T cells are essential mediators of protective immunity to viral infection and malignant tumours and are a key target of immunotherapy approaches. However, prolonged exposure to cognate antigens often attenuates the effector capacity of T cells and limits their therapeutic potential1-4. This process, known as T cell exhaustion or dysfunction1, is manifested by epigenetically enforced changes in gene regulation that reduce the expression of cytokines and effector molecules and upregulate the expression of inhibitory receptors such as programmed cell-death 1 (PD-1)5-8. The underlying molecular mechanisms that induce and stabilize the phenotypic and functional features of exhausted T cells remain poorly understood9-12. Here we report that the development and maintenance of populations of exhausted T cells in mice requires the thymocyte selection-associated high mobility group box (TOX) protein13-15. TOX is induced by high antigen stimulation of the T cell receptor and correlates with the presence of an exhausted phenotype during chronic infections with lymphocytic choriomeningitis virus in mice and hepatitis C virus in humans. Removal of its DNA-binding domain reduces the expression of PD-1 at the mRNA and protein level, augments the production of cytokines and results in a more polyfunctional T cell phenotype. T cells with this deletion initially mediate increased effector function and cause more severe immunopathology, but ultimately undergo a massive decline in their quantity, notably among the subset of TCF-1+ self-renewing T cells. Altogether, we show that TOX is a critical factor for the normal progression of T cell dysfunction and the maintenance of exhausted T cells during chronic infection, and provide a link between the suppression of effector function intrinsic to CD8 T cells and protection against immunopathology.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/patología , Hepatitis C Crónica/inmunología , Hepatitis C Crónica/virología , Proteínas del Grupo de Alta Movilidad/metabolismo , Proteínas de Homeodominio/metabolismo , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Animales , Proliferación Celular , Enfermedad Crónica , Citocinas/inmunología , Citocinas/metabolismo , Epigénesis Genética , Femenino , Regulación de la Expresión Génica/inmunología , Hepacivirus/inmunología , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Humanos , Memoria Inmunológica , Virus de la Coriomeningitis Linfocítica/inmunología , Masculino , Ratones , Fenotipo , Timocitos/citología , Timocitos/inmunología , Transcripción Genética
3.
Nucleic Acids Res ; 49(D1): D831-D847, 2021 01 08.
Artículo en Inglés | MEDLINE | ID: mdl-33037820

RESUMEN

Bgee is a database to retrieve and compare gene expression patterns in multiple animal species, produced by integrating multiple data types (RNA-Seq, Affymetrix, in situ hybridization, and EST data). It is based exclusively on curated healthy wild-type expression data (e.g., no gene knock-out, no treatment, no disease), to provide a comparable reference of normal gene expression. Curation includes very large datasets such as GTEx (re-annotation of samples as 'healthy' or not) as well as many small ones. Data are integrated and made comparable between species thanks to consistent data annotation and processing, and to calls of presence/absence of expression, along with expression scores. As a result, Bgee is capable of detecting the conditions of expression of any single gene, accommodating any data type and species. Bgee provides several tools for analyses, allowing, e.g., automated comparisons of gene expression patterns within and between species, retrieval of the prefered conditions of expression of any gene, or enrichment analyses of conditions with expression of sets of genes. Bgee release 14.1 includes 29 animal species, and is available at https://bgee.org/ and through its Bioconductor R package BgeeDB.


Asunto(s)
Curaduría de Datos , Bases de Datos Genéticas , Transcriptoma/genética , Animales , Regulación de la Expresión Génica , Anotación de Secuencia Molecular , Interfaz Usuario-Computador
4.
Proc Natl Acad Sci U S A ; 116(40): 20070-20076, 2019 10 01.
Artículo en Inglés | MEDLINE | ID: mdl-31530725

RESUMEN

T cell maintenance in chronic infection and cancer follows a hierarchical order. Short-lived effector CD8 T cells are constitutively replaced from a proliferation-competent Tcf1-expressing progenitor population. This occurs spontaneously at low levels and increases in magnitude upon blocking PD-1 signaling. We explore how CD4 T cell help controls transition and survival of the progenitors and their progeny by utilizing single-cell RNA sequencing. Unexpectedly, absence of CD4 help caused reductions in cell numbers only among terminally differentiated cells while proliferation-competent progenitor cells remained unaffected with regard to their numbers and their overall phenotype. In fact, upon restoration of a functional CD4 compartment, the progenitors began to regenerate the effector CD8 T cells. Thus, unlike memory T cells for which secondary expansion requires CD4 T cell help, this is not a necessity for proliferation-competent progenitor cells in dysfunctional populations. Our data therefore reveals that proliferation-competent cells in dysfunctional populations show a previously unrecognized uncoupling of CD4 T cell help that is otherwise required by conventional memory T cells.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Activación de Linfocitos/inmunología , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Movimiento Celular , Proliferación Celular , Células Cultivadas , Epítopos de Linfocito T/inmunología , Ratones , Ratones Transgénicos , Fenotipo , Transducción de Señal
5.
Nat Biotechnol ; 41(6): 788-793, 2023 06.
Artículo en Inglés | MEDLINE | ID: mdl-36593397

RESUMEN

Spatial transcriptomics and proteomics provide complementary information that independently transformed our understanding of complex biological processes. However, experimental integration of these modalities is limited. To overcome this, we developed Spatial PrOtein and Transcriptome Sequencing (SPOTS) for high-throughput simultaneous spatial transcriptomics and protein profiling. Compared with unimodal measurements, SPOTS substantially improves signal resolution and cell clustering and enhances the discovery power in differential gene expression analysis across tissue regions.


Asunto(s)
Perfilación de la Expresión Génica , Transcriptoma , Transcriptoma/genética , Proteínas , Proteómica , Análisis por Conglomerados
6.
Sci Immunol ; 7(77): eabp9553, 2022 11 11.
Artículo en Inglés | MEDLINE | ID: mdl-36332011

RESUMEN

Resident T lymphocytes (TRM) protect tissues during pathogen reexposure. Although TRM phenotype and restricted migratory pattern are established, we have a limited understanding of their response kinetics, stability, and turnover during reinfections. Such characterizations have been restricted by the absence of in vivo fate-mapping systems. We generated two mouse models, one to stably mark CD103+ T cells (a marker of TRM cells) and the other to specifically deplete CD103- T cells. Using these models, we observed that intestinal CD103+ T cells became activated during viral or bacterial reinfection, remained organ-confined, and retained their original phenotype but failed to reexpand. Instead, the population was largely rejuvenated by CD103+ T cells formed de novo during reinfections. This pattern remained unchanged upon deletion of antigen-specific circulating T cells, indicating that the lack of expansion was not due to competition with circulating subsets. Thus, although intestinal CD103+ resident T cells survived long term without antigen, they lacked the ability of classical memory T cells to reexpand. This indicated that CD103+ T cell populations could not autonomously maintain themselves. Instead, their numbers were sustained during reinfection via de novo formation from CD103- precursors. Moreover, in contrast to CD103- cells, which require antigen plus inflammation for their activation, CD103+ TRM became fully activated follwing exposure to inflammation alone. Together, our data indicate that primary CD103+ resident memory T cells lack secondary expansion potential and require CD103- precursors for their long-term maintenance.


Asunto(s)
Coinfección , Memoria Inmunológica , Ratones , Animales , Reinfección , Linfocitos T CD8-positivos , Células T de Memoria , Inflamación
7.
Nat Commun ; 12(1): 569, 2021 01 25.
Artículo en Inglés | MEDLINE | ID: mdl-33495472

RESUMEN

Single-cell RNA sequencing in principle offers unique opportunities to improve the efficacy of contemporary T-cell based immunotherapy against cancer. The use of high-quality single-cell data will aid our incomplete understanding of molecular programs determining the differentiation and functional heterogeneity of cytotoxic T lymphocytes (CTLs), allowing for optimal therapeutic design. So far, a major obstacle to high depth single-cell analysis of CTLs is the minute amount of RNA available, leading to low capturing efficacy. Here, to overcome this, we tailor a droplet-based approach for high-throughput analysis (tDrop-seq) and a plate-based method for high-performance in-depth CTL analysis (tSCRB-seq). The latter gives, on average, a 15-fold higher number of captured transcripts per gene compared to droplet-based technologies. The improved dynamic range of gene detection gives tSCRB-seq an edge in resolution sensitive downstream applications such as graded high confidence gene expression measurements and cluster characterization. We demonstrate the power of tSCRB-seq by revealing the subpopulation-specific expression of co-inhibitory and co-stimulatory receptor targets of key importance for immunotherapy.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Análisis de Secuencia de ARN/métodos , Análisis de la Célula Individual/métodos , Linfocitos T Citotóxicos/metabolismo , Animales , Perfilación de la Expresión Génica/métodos , Humanos , Ratones , ARN/genética , ARN Mensajero/genética , Reproducibilidad de los Resultados , Linfocitos T Citotóxicos/citología
8.
J Exp Med ; 213(9): 1819-34, 2016 08 22.
Artículo en Inglés | MEDLINE | ID: mdl-27455951

RESUMEN

Chronic infections induce T cells showing impaired cytokine secretion and up-regulated expression of inhibitory receptors such as PD-1. What determines the acquisition of this chronic phenotype and how it impacts T cell function remain vaguely understood. Using newly generated recombinant antigen variant-expressing chronic lymphocytic choriomeningitis virus (LCMV) strains, we uncovered that T cell differentiation and acquisition of a chronic or exhausted phenotype depend critically on the frequency of T cell receptor (TCR) engagement and less significantly on the strength of TCR stimulation. In fact, we noted that low-level antigen exposure promotes the formation of T cells with an acute phenotype in chronic infections. Unexpectedly, we found that T cell populations with an acute or chronic phenotype are maintained equally well in chronic infections and undergo comparable primary and secondary expansion. Thus, our observations contrast with the view that T cells with a typical chronic infection phenotype are severely functionally impaired and rapidly transition into a terminal stage of differentiation. Instead, our data unravel that T cells primarily undergo a form of phenotypic and functional differentiation in the early phase of a chronic LCMV infection without inheriting a net survival or expansion deficit, and we demonstrate that the acquired chronic phenotype transitions into the memory T cell compartment.


Asunto(s)
Antígenos Virales/sangre , Coriomeningitis Linfocítica/inmunología , Linfocitos T/fisiología , Animales , Antígenos CD/análisis , Diferenciación Celular , Supervivencia Celular , Enfermedad Crónica , Subunidad alfa del Receptor de Interleucina-7/análisis , Activación de Linfocitos , Virus de la Coriomeningitis Linfocítica/inmunología , Ratones , Ratones Endogámicos C57BL , Fenotipo , Receptor de Muerte Celular Programada 1/análisis , Receptores de Antígenos de Linfocitos T/fisiología , Linfocitos T/citología , Proteína del Gen 3 de Activación de Linfocitos
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