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1.
Immunity ; 45(5): 1148-1161, 2016 11 15.
Artículo en Inglés | MEDLINE | ID: mdl-27851915

RESUMEN

The impact of epigenetics on the differentiation of memory T (Tmem) cells is poorly defined. We generated deep epigenomes comprising genome-wide profiles of DNA methylation, histone modifications, DNA accessibility, and coding and non-coding RNA expression in naive, central-, effector-, and terminally differentiated CD45RA+ CD4+ Tmem cells from blood and CD69+ Tmem cells from bone marrow (BM-Tmem). We observed a progressive and proliferation-associated global loss of DNA methylation in heterochromatic parts of the genome during Tmem cell differentiation. Furthermore, distinct gradually changing signatures in the epigenome and the transcriptome supported a linear model of memory development in circulating T cells, while tissue-resident BM-Tmem branched off with a unique epigenetic profile. Integrative analyses identified candidate master regulators of Tmem cell differentiation, including the transcription factor FOXP1. This study highlights the importance of epigenomic changes for Tmem cell biology and demonstrates the value of epigenetic data for the identification of lineage regulators.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular/inmunología , Epigénesis Genética/inmunología , Epigenómica/métodos , Memoria Inmunológica/inmunología , Femenino , Citometría de Flujo , Perfilación de la Expresión Génica/métodos , Humanos , Aprendizaje Automático , Reacción en Cadena de la Polimerasa , Transcriptoma
2.
Eur J Immunol ; 52(5): 737-752, 2022 05.
Artículo en Inglés | MEDLINE | ID: mdl-35245389

RESUMEN

Resident memory T lymphocytes (TRM ) of epithelial tissues and the Bm protect their host tissue. To what extent these cells are mobilized and contribute to systemic immune reactions is less clear. Here, we show that in secondary immune reactions to the measles-mumps-rubella (MMR) vaccine, CD4+ TRM are mobilized into the blood within 16 to 48 h after immunization in humans. This mobilization of TRM is cognate: TRM recognizing other antigens are not mobilized, unless they cross-react with the vaccine. We also demonstrate through methylome analyses that TRM are mobilized from the Bm. These mobilized cells make significant contribution to the systemic immune reaction, as evidenced by their T-cell receptor Vß clonotypes represented among the newly generated circulating memory T-cells, 14 days after vaccination. Thus, TRM of the Bm confer not only local, but also systemic immune memory.


Asunto(s)
Memoria Inmunológica , Vacunas , Médula Ósea , Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Humanos
3.
Eur J Immunol ; 49(6): 966-968, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30673129

RESUMEN

It is a matter of current debate whether the bone marrow is a hub for circulating memory T lymphocytes and/or the home of resident memory T lymphocytes. Here we demonstrate for CD69+ murine CD8+ , and CD69+ murine and human CD4+ memory T lymphocytes of the bone marrow, making up between 30 and 60% of bone marrow memory T lymphocytes, that they express the gene expression signature of tissue-resident memory T lymphocytes. This suggests that a substantial proportion of bone marrow memory T lymphocytes are resident. It adds to previous evidence that bone marrow memory T cells are resting in terms of mobility and proliferation, and maintain exclusive long-term memory to distinct, systemic antigens.


Asunto(s)
Células de la Médula Ósea/inmunología , Memoria Inmunológica/inmunología , Bazo/inmunología , Subgrupos de Linfocitos T/inmunología , Animales , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Humanos , Lectinas Tipo C/inmunología , Ratones , Bazo/citología , Transcriptoma/inmunología
4.
Front Immunol ; 12: 624013, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33828548

RESUMEN

Studies in animal models have shown that skin tissue-resident memory T (TRM) cells provide enhanced and immediate effector function at the site of infection. However, analyses of skin TRM cells in humans have been hindered by the lack of an optimized isolation protocol. Here, we present a combinatorial strategy-the 6-h collagenase IV digestion and gentle tissue dissociation - for rapid and efficient isolation of skin TRM cells with skin tissue-specific immune features. In comparison with paired blood circulating memory T cells, these ex vivo isolated skin T cells express typical TRM cell markers and display higher polyfunctional properties. Moreover, these isolated cells can also be assessed for longer periods of time in ex vivo cultures. Thus, the optimized isolation protocol provides a valuable tool for further understanding of human skin TRM cells, especially for direct comparison with peripheral blood T cells at the same sample collection time.


Asunto(s)
Separación Celular , Citometría de Flujo , Memoria Inmunológica , Piel/inmunología , Linfocitos T/inmunología , Anciano , Biomarcadores/metabolismo , Supervivencia Celular , Células Cultivadas , Colagenasas/metabolismo , Citocinas/metabolismo , Femenino , Humanos , Inmunofenotipificación , Activación de Linfocitos , Masculino , Persona de Mediana Edad , Fenotipo , Piel/citología , Piel/metabolismo , Linfocitos T/metabolismo , Factores de Tiempo , Flujo de Trabajo
5.
Arthritis Res Ther ; 17: 356, 2015 Dec 10.
Artículo en Inglés | MEDLINE | ID: mdl-26653844

RESUMEN

INTRODUCTION: Despite the broad spectrum of antirheumatic drugs, RA is still not well controlled in up to 30-50 % of patients. Inhibition of JAK kinases by means of the pan-JAK inhibitor tofacitinib has demonstrated to be effective even in difficult-to-treat patients. Here, we discuss whether the efficacy of JAK inhibition can be improved by simultaneously inhibiting SYK kinase, since both kinases mediate complementary and non-redundant pathways in RA. METHODS: Efficacy of dual JAK + SYK inhibition with selective small molecule inhibitors was evaluated in chronic G6PI-induced arthritis, a non-self-remitting and destructive arthritis model in mice. Clinical and histopathological scores, as well as cytokine and anti-G6PI antibody production were assessed in both preventive and curative protocols. Potential immunotoxicity was also evaluated in G6PI-induced arthritis and in a 28-day TDAR model, by analysing the effects of JAK + SYK inhibition on hematological parameters, lymphoid organs, leukocyte subsets and cell function. RESULTS: Simultaneous JAK + SYK inhibition completely prevented mice from developing arthritis. This therapeutic strategy was also very effective in ameliorating already established arthritis. Dual kinase inhibition immediately resulted in greatly decreased clinical and histopathological scores and led to disease remission in over 70 % of the animals. In contrast, single JAK inhibition and anti-TNF therapy (etanercept) were able to stop disease progression but not to revert it. Dual kinase inhibition decreased Treg and NK cell counts to the same extent as single JAK inhibition but overall cytotoxicity remained intact. Interestingly, treatment discontinuation rapidly reversed such immune cell reduction without compromising clinical efficacy, suggesting long-lasting curative effects. Dual kinase inhibition reduced the Th1/Th17 cytokine cascade and the differentiation and function of joint cells, in particular osteoclasts and fibroblast-like synoviocytes. CONCLUSIONS: Concurrent JAK + SYK inhibition resulted in higher efficacy than single kinase inhibition and TNF blockade in a chronic and severe arthritis model. Thus, blockade of multiple immune signals with dual JAK + SYK inhibition represents a reasonable therapeutic strategy for RA, in particular in patients with inadequate responses to current treatments. Our data supports the multiplicity of events underlying this heterogeneous and complex disease.


Asunto(s)
Antirreumáticos/administración & dosificación , Artritis Experimental/patología , Artritis Reumatoide/patología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Quinasas Janus/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/administración & dosificación , Proteínas Tirosina Quinasas/antagonistas & inhibidores , Animales , Artritis Experimental/inmunología , Artritis Reumatoide/inmunología , Ciclohexilaminas/administración & dosificación , Modelos Animales de Enfermedad , Quimioterapia Combinada/métodos , Ensayo de Inmunoadsorción Enzimática , Citometría de Flujo , Inmunofenotipificación , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos DBA , Piperidinas/administración & dosificación , Pirimidinas/administración & dosificación , Pirroles/administración & dosificación , Quinasa Syk
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