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1.
Nat Immunol ; 23(7): 1121-1131, 2022 07.
Artículo en Inglés | MEDLINE | ID: mdl-35761084

RESUMEN

Tissue-resident memory T cells (TRM cells) provide protective immunity, but the contributions of specific tissue environments to TRM cell differentiation and homeostasis are not well understood. In the present study, the diversity of gene expression and genome accessibility by mouse CD8+ TRM cells from distinct organs that responded to viral infection revealed both shared and tissue-specific transcriptional and epigenetic signatures. TRM cells in the intestine and salivary glands expressed transforming growth factor (TGF)-ß-induced genes and were maintained by ongoing TGF-ß signaling, whereas those in the fat, kidney and liver were not. Constructing transcriptional-regulatory networks identified the transcriptional repressor Hic1 as a critical regulator of TRM cell differentiation in the small intestine and showed that Hic1 overexpression enhanced TRM cell differentiation and protection from infection. Provision of a framework for understanding how CD8+ TRM cells adapt to distinct tissue environments, and identification of tissue-specific transcriptional regulators mediating these adaptations, inform strategies to boost protective memory responses at sites most vulnerable to infection.


Asunto(s)
Linfocitos T CD8-positivos , Memoria Inmunológica , Animales , Diferenciación Celular/genética , Epigénesis Genética , Ratones , Factores de Transcripción/metabolismo , Factor de Crecimiento Transformador beta/metabolismo
2.
Immunity ; 56(5): 959-978.e10, 2023 05 09.
Artículo en Inglés | MEDLINE | ID: mdl-37040762

RESUMEN

Although the importance of genome organization for transcriptional regulation of cell-fate decisions and function is clear, the changes in chromatin architecture and how these impact effector and memory CD8+ T cell differentiation remain unknown. Using Hi-C, we studied how genome configuration is integrated with CD8+ T cell differentiation during infection and investigated the role of CTCF, a key chromatin remodeler, in modulating CD8+ T cell fates through CTCF knockdown approaches and perturbation of specific CTCF-binding sites. We observed subset-specific changes in chromatin organization and CTCF binding and revealed that weak-affinity CTCF binding promotes terminal differentiation of CD8+ T cells through the regulation of transcriptional programs. Further, patients with de novo CTCF mutations had reduced expression of the terminal-effector genes in peripheral blood lymphocytes. Therefore, in addition to establishing genome architecture, CTCF regulates effector CD8+ T cell heterogeneity through altering interactions that regulate the transcription factor landscape and transcriptome.


Asunto(s)
Cromatina , Proteínas Represoras , Humanos , Sitios de Unión , Factor de Unión a CCCTC/metabolismo , Linfocitos T CD8-positivos/metabolismo , ADN/metabolismo , Unión Proteica , Proteínas Represoras/genética , Proteínas Represoras/metabolismo
3.
Nat Immunol ; 18(5): 573-582, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28288100

RESUMEN

Dynamic changes in the expression of transcription factors (TFs) can influence the specification of distinct CD8+ T cell fates, but the observation of equivalent expression of TFs among differentially fated precursor cells suggests additional underlying mechanisms. Here we profiled the genome-wide histone modifications, open chromatin and gene expression of naive, terminal-effector, memory-precursor and memory CD8+ T cell populations induced during the in vivo response to bacterial infection. Integration of these data suggested that the expression and binding of TFs contributed to the establishment of subset-specific enhancers during differentiation. We developed a new bioinformatics method using the PageRank algorithm to reveal key TFs that influence the generation of effector and memory populations. The TFs YY1 and Nr3c1, both constitutively expressed during CD8+ T cell differentiation, regulated the formation of terminal-effector cell fates and memory-precursor cell fates, respectively. Our data define the epigenetic landscape of differentiation intermediates and facilitate the identification of TFs with previously unappreciated roles in CD8+ T cell differentiation.


Asunto(s)
Linfocitos T CD8-positivos/fisiología , Epigénesis Genética , Listeriosis/inmunología , Receptores de Glucocorticoides/metabolismo , Subgrupos de Linfocitos T/fisiología , Factor de Transcripción YY1/metabolismo , Animales , Linfocitos T CD8-positivos/microbiología , Diferenciación Celular/genética , Biología Computacional , Elementos de Facilitación Genéticos/genética , Perfilación de la Expresión Génica , Histonas/metabolismo , Memoria Inmunológica/genética , Ratones , Ratones Endogámicos C57BL , Receptores de Glucocorticoides/genética , Subgrupos de Linfocitos T/microbiología , Factor de Transcripción YY1/genética
4.
Immunity ; 52(5): 808-824.e7, 2020 05 19.
Artículo en Inglés | MEDLINE | ID: mdl-32433949

RESUMEN

Tissue-resident memory CD8+ T cells (Trm) provide host protection through continuous surveillance of non-lymphoid tissues. Using single-cell RNA-sequencing (scRNA-seq) and genetic reporter mice, we identified discrete lineages of intestinal antigen-specific CD8+ T cells, including a Blimp1hiId3lo tissue-resident effector cell population most prominent in the early phase of acute viral and bacterial infections and a molecularly distinct Blimp1loId3hi tissue-resident memory population that subsequently accumulated at later infection time points. These Trm populations exhibited distinct cytokine production, secondary memory potential, and transcriptional programs including differential roles for transcriptional regulators Blimp1, T-bet, Id2, and Id3 in supporting and maintaining intestinal Trm. Extending our analysis to malignant tissue, we also identified discrete populations of effector-like and memory-like CD8+ T cell populations with tissue-resident gene-expression signatures that shared features of terminally exhausted and progenitor-exhausted T cells, respectively. Our findings provide insight into the development and functional heterogeneity of Trm cells, which has implications for enhancing vaccination and immunotherapy approaches.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Neoplasias/terapia , Animales , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Células Cultivadas , Inmunoterapia/métodos , Proteína 2 Inhibidora de la Diferenciación/genética , Proteína 2 Inhibidora de la Diferenciación/inmunología , Proteína 2 Inhibidora de la Diferenciación/metabolismo , Proteínas Inhibidoras de la Diferenciación/genética , Proteínas Inhibidoras de la Diferenciación/inmunología , Proteínas Inhibidoras de la Diferenciación/metabolismo , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Neoplasias/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/genética , Factor 1 de Unión al Dominio 1 de Regulación Positiva/inmunología , Factor 1 de Unión al Dominio 1 de Regulación Positiva/metabolismo
7.
PLoS Comput Biol ; 18(9): e1010116, 2022 09.
Artículo en Inglés | MEDLINE | ID: mdl-36156073

RESUMEN

Transcription factors (TFs) are crucial for regulating cell differentiation during the development of the immune system. However, the key TFs for orchestrating the specification of distinct immune cells are not fully understood. Here, we integrated the transcriptomic and epigenomic measurements in 73 mouse and 61 human primary cell types, respectively, that span the immune cell differentiation pathways. We constructed the cell-type-specific transcriptional regulatory network and assessed the global importance of TFs based on the Taiji framework, which is a method we have previously developed that can infer the global impact of TFs using integrated transcriptomic and epigenetic data. Integrative analysis across cell types revealed putative driver TFs in cell lineage-specific differentiation in both mouse and human systems. We have also identified TF combinations that play important roles in specific developmental stages. Furthermore, we validated the functions of predicted novel TFs in murine CD8+ T cell differentiation and showed the importance of Elf1 and Prdm9 in the effector versus memory T cell fate specification and Kdm2b and Tet3 in promoting differentiation of CD8+ tissue resident memory (Trm) cells, validating the approach. Thus, we have developed a bioinformatic approach that provides a global picture of the regulatory mechanisms that govern cellular differentiation in the immune system and aids the discovery of novel mechanisms in cell fate decisions.


Asunto(s)
Redes Reguladoras de Genes , Factores de Transcripción , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Biología Computacional , N-Metiltransferasa de Histona-Lisina , Humanos , Ratones , Factores de Transcripción/genética , Factores de Transcripción/metabolismo
8.
Nature ; 552(7684): 253-257, 2017 12 14.
Artículo en Inglés | MEDLINE | ID: mdl-29211713

RESUMEN

Tissue-resident memory CD8+ T (TRM) cells are found at common sites of pathogen exposure, where they elicit rapid and robust protective immune responses. However, the molecular signals that control TRM cell differentiation and homeostasis are not fully understood. Here we show that mouse TRM precursor cells represent a unique CD8+ T cell subset that is distinct from the precursors of circulating memory cell populations at the levels of gene expression and chromatin accessibility. Using computational and pooled in vivo RNA interference screens, we identify the transcription factor Runx3 as a key regulator of TRM cell differentiation and homeostasis. Runx3 was required to establish TRM cell populations in diverse tissue environments, and supported the expression of crucial tissue-residency genes while suppressing genes associated with tissue egress and recirculation. Furthermore, we show that human and mouse tumour-infiltrating lymphocytes share a core tissue-residency gene-expression signature with TRM cells that is associated with Runx3 activity. In a mouse model of adoptive T cell therapy for melanoma, Runx3-deficient CD8+ tumour-infiltrating lymphocytes failed to accumulate in tumours, resulting in greater rates of tumour growth and mortality. Conversely, overexpression of Runx3 enhanced tumour-specific CD8+ T cell abundance, delayed tumour growth, and prolonged survival. In addition to establishing Runx3 as a central regulator of TRM cell differentiation, these results provide insight into the signals that promote T cell residency in non-lymphoid sites, which could be used to enhance vaccine efficacy or adoptive cell therapy treatments that target cancer.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Subunidad alfa 3 del Factor de Unión al Sitio Principal/metabolismo , Memoria Inmunológica , Melanoma/inmunología , Especificidad de Órganos/inmunología , Traslado Adoptivo , Animales , Linfocitos T CD8-positivos/citología , Diferenciación Celular , Proliferación Celular , Cromatina/genética , Cromatina/metabolismo , Subunidad alfa 3 del Factor de Unión al Sitio Principal/deficiencia , Subunidad alfa 3 del Factor de Unión al Sitio Principal/genética , Modelos Animales de Enfermedad , Femenino , Regulación de la Expresión Génica , Homeostasis , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Melanoma/genética , Melanoma/patología , Melanoma/terapia , Ratones , Especificidad de Órganos/genética , Análisis de Supervivencia , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
9.
Mol Cell ; 58(3): 453-67, 2015 May 07.
Artículo en Inglés | MEDLINE | ID: mdl-25866244

RESUMEN

Phosphoinositides (PI) are important signaling molecules in the nucleus that influence gene expression. However, if and how nuclear PI directly affects the transcriptional machinery is not known. We report that the lipid kinase PIP4K2B regulates nuclear PI5P and the expression of myogenic genes during myoblast differentiation. A targeted screen for PI interactors identified the PHD finger of TAF3, a TATA box binding protein-associated factor with important roles in transcription regulation, pluripotency, and differentiation. We show that the PI interaction site is distinct from the known H3K4me3 binding region of TAF3 and that PI binding modulates association of TAF3 with H3K4me3 in vitro and with chromatin in vivo. Analysis of TAF3 mutants indicates that TAF3 transduces PIP4K2B-mediated alterations in PI into changes in specific gene transcription. Our study reveals TAF3 as a direct target of nuclear PI and further illustrates the importance of basal transcription components as signal transducers.


Asunto(s)
Núcleo Celular/metabolismo , Proteínas de Homeodominio/metabolismo , Fosfatidilinositoles/metabolismo , Transcripción Genética , Secuencia de Aminoácidos , Animales , Diferenciación Celular/genética , Línea Celular , Núcleo Celular/genética , Electroforesis en Gel de Poliacrilamida , Perfilación de la Expresión Génica , Histonas/metabolismo , Proteínas de Homeodominio/genética , Lisina/metabolismo , Metilación , Ratones , Antígenos de Histocompatibilidad Menor , Datos de Secuencia Molecular , Mutación , Mioblastos/citología , Mioblastos/metabolismo , Análisis de Secuencia por Matrices de Oligonucleótidos , Fosfotransferasas (Aceptor de Grupo Alcohol)/genética , Fosfotransferasas (Aceptor de Grupo Alcohol)/metabolismo , Unión Proteica , Interferencia de ARN , Homología de Secuencia de Aminoácido , Factores Asociados con la Proteína de Unión a TATA , Factor de Transcripción TFIID/genética , Factor de Transcripción TFIID/metabolismo , Pez Cebra/embriología , Pez Cebra/genética , Pez Cebra/metabolismo
10.
Proc Natl Acad Sci U S A ; 117(41): 25667-25678, 2020 10 13.
Artículo en Inglés | MEDLINE | ID: mdl-32978300

RESUMEN

Memory CD8 T cells provide durable protection against diverse intracellular pathogens and can be broadly segregated into distinct circulating and tissue-resident populations. Paradigmatic studies have demonstrated that circulating memory cells can be further divided into effector memory (Tem) and central memory (Tcm) populations based on discrete functional characteristics. Following resolution of infection, we identified a persisting antigen-specific CD8 T cell population that was terminally fated with potent effector function but maintained memory T cell qualities and conferred robust protection against reinfection. Notably, this terminally differentiated effector memory CD8 T cell population (terminal-Tem) was conflated within the conventional Tem population, prompting redefinition of the classical characteristics of Tem cells. Murine terminal-Tem were transcriptionally, functionally, and developmentally unique compared to Tem cells. Through mass cytometry and single-cell RNA sequencing (RNA-seq) analyses of human peripheral blood from healthy individuals, we also identified an analogous terminal-Tem population of CD8 T cells that was transcriptionally distinct from Tem and Tcm Key findings from this study show that parsing of terminal-Tem from conventionally defined Tem challenge the reported characteristics of Tem biology, including enhanced presence in lymphoid tissues, robust IL-2 production, and recall potential, greater than expected homeostatic fitness, refined transcription factor dependencies, and a distinct molecular phenotype. Classification of terminal-Tem and clarification of Tem biology hold broad implications for understanding the molecular regulation of memory cell states and harnessing immunological memory to improve immunotherapies.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Memoria Inmunológica/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Linaje de la Célula/inmunología , Células Cultivadas , Humanos , Ratones
11.
bioRxiv ; 2023 Apr 15.
Artículo en Inglés | MEDLINE | ID: mdl-37090503

RESUMEN

CD8 + T cells with stem cell-like properties (T SCM ) sustain adaptive immunity to intracellular pathogens and tumors. However, the developmental origins and chromatin regulatory factors (CRFs) that establish their differentiation are unclear. Using an RNA interference screen of all CRFs we discovered the histone methylase Mll1 was required during T cell receptor (TCR) stimulation for development of a T SCM precursor state and mature memory (T MEM ) cells, but not short-lived or transitory effector cell-like states, in response to viral infections and tumors. Mll1 was essential for widespread de novo deposition of histone H3 lysine 4 trimethylation (H3K4me3) upon TCR stimulation, which accounted for 70% of all activation-induced sites in mature T MEM cells. Mll1 promoted both H3K4me3 deposition and reduced TCR-induced Pol II pausing at genes whose single-cell transcriptional dynamics explained trajectories into nascent T SCM precursor states during viral infection. Our results suggest Mll1-dependent control of Pol II elongation and H3K4me3 establishes and maintains differentiation of CD8 + T SCM cell states.

12.
J Exp Med ; 218(8)2021 08 02.
Artículo en Inglés | MEDLINE | ID: mdl-34037670

RESUMEN

In response to infection, pathogen-specific CD8 T cells differentiate into functionally diverse effector and memory T cell populations critical for resolving disease and providing durable immunity. Through small-molecule inhibition, RNAi studies, and induced genetic deletion, we reveal an essential role for the chromatin modifier and BET family member BRD4 in supporting the differentiation and maintenance of terminally fated effector CD8 T cells during infection. BRD4 bound diverse regulatory regions critical to effector T cell differentiation and controlled transcriptional activity of terminal effector-specific super-enhancers in vivo. Consequentially, induced deletion of Brd4 or small molecule-mediated BET inhibition impaired maintenance of a terminal effector T cell phenotype. BRD4 was also required for terminal differentiation of CD8 T cells in the tumor microenvironment in murine models, which we show has implications for immunotherapies. Taken together, these data reveal an unappreciated requirement for BRD4 in coordinating activity of cis regulatory elements to control CD8 T cell fate and lineage stability.


Asunto(s)
Linfocitos T CD8-positivos/citología , Diferenciación Celular/inmunología , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Virosis/inmunología , Animales , Linfocitos T CD8-positivos/inmunología , Cromatina/metabolismo , Elementos de Facilitación Genéticos/genética , Ratones Noqueados , Neoplasias/inmunología , Neoplasias/patología , Proteínas Nucleares/deficiencia , Unión Proteica , Interferencia de ARN , Factores de Transcripción/deficiencia , Transcripción Genética
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