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1.
Proc Natl Acad Sci U S A ; 115(38): E8939-E8947, 2018 09 18.
Artículo en Inglés | MEDLINE | ID: mdl-30126987

RESUMEN

Identifying novel pathways that promote robust function and longevity of cytotoxic T cells has promising potential for immunotherapeutic strategies to combat cancer and chronic infections. We show that sprouty 1 and 2 (Spry1/2) molecules regulate the survival and function of memory CD8+ T cells. Spry1/2 double-knockout (DKO) ovalbumin (OVA)-specific CD8+ T cells (OT-I cells) mounted more vigorous autoimmune diabetes than WT OT-I cells when transferred to mice expressing OVA in their pancreatic ß-islets. To determine the consequence of Spry1/2 deletion on effector and memory CD8+ T cell development and function, we used systemic infection with lymphocytic choriomeningitis virus (LCMV) Armstrong. Spry1/2 DKO LCMV gp33-specific P14 CD8+ T cells survive contraction better than WT cells and generate significantly more polyfunctional memory T cells. The larger number of Spry1/2 DKO memory T cells displayed enhanced infiltration into infected tissue, demonstrating that absence of Spry1/2 can result in increased recall capacity. Upon adoptive transfer into naive hosts, Spry1/2 DKO memory T cells controlled Listeria monocytogenes infection better than WT cells. The enhanced formation of more functional Spry1/2 DKO memory T cells was associated with significantly reduced mTORC1 activity and glucose uptake. Reduced p-AKT, p-FoxO1/3a, and T-bet expression was also consistent with enhanced survival and memory accrual. Collectively, loss of Spry1/2 enhances the survival of effector CD8+ T cells and results in the formation of more protective memory cells. Deleting Spry1/2 in antigen-specific CD8+ T cells may have therapeutic potential for enhancing the survival and functionality of effector and memory CD8+ T cells in vivo.


Asunto(s)
Proteínas Adaptadoras Transductoras de Señales/inmunología , Linfocitos T CD8-positivos/fisiología , Memoria Inmunológica/genética , Péptidos y Proteínas de Señalización Intracelular/inmunología , Activación de Linfocitos/genética , Proteínas de la Membrana/inmunología , Fosfoproteínas/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Traslado Adoptivo/métodos , Animales , Linfocitos T CD8-positivos/trasplante , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Diabetes Mellitus Tipo 1/sangre , Diabetes Mellitus Tipo 1/inmunología , Diabetes Mellitus Tipo 1/orina , Modelos Animales de Enfermedad , Femenino , Humanos , Memoria Inmunológica/inmunología , Péptidos y Proteínas de Señalización Intracelular/genética , Listeria monocytogenes/inmunología , Listeria monocytogenes/aislamiento & purificación , Listeriosis/inmunología , Listeriosis/microbiología , Listeriosis/terapia , Activación de Linfocitos/inmunología , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Fosfoproteínas/genética , Proteínas Serina-Treonina Quinasas , Quimera por Trasplante
2.
J Immunol ; 195(6): 2624-32, 2015 Sep 15.
Artículo en Inglés | MEDLINE | ID: mdl-26246142

RESUMEN

Impaired functionality of dendritic cells (DCs) significantly contributes to decreased adaptive immune responses in aged hosts. The expression of MHC-peptide on the DC surface is the critical first step in T cell priming, but few studies have addressed the effect of aging on Ag acquisition, processing, and presentation by DCs. In this study, we show that aged murine DCs were less efficient in the cross-presentation of cell-associated Ag and subsequently in the cross-priming of CD8(+) T cells than were their young counterparts. The decreased cross-presentation was associated with a reduction in the frequency of CD8α DCs and merocytic (CD8α(-)CD11b(-))DCs that could endocytose cell-associated Ag, as well as the number and the size of the endocytosed particles in the DC that did internalize cell-associated materials. Mechanistically, phagocytic capacity has been associated with mitochondrial activity and membrane potential (Δψm). Aged DCs exhibited profound signs of mitochondrial dysfunction, illustrated by lower Δψm, reduced ATP turnover and coupling efficiency, decreased baseline oxidative phosphorylation, and greater proton leak and reactive oxygen species (ROS) production. Mimicking the aged metabolic phenotype in young DCs by pharmacologic manipulation indicated that the reductions in Δψm and ATP impeded the phagocytic capacity whereas ROS interfered with a later step in the cross-presentation process. Conversely, in vitro scavenging of ROS partially restored cross-presentation by aged DCs. Taken together, these data suggest that improvement of aged DC functionality might be feasible in the elderly by targeting metabolic dysfunction or its downstream sequelae, thereby opening new avenues for enhancing vaccine efficiency in this population.


Asunto(s)
Reactividad Cruzada/inmunología , Células Dendríticas/inmunología , Inmunosenescencia/fisiología , Mitocondrias/inmunología , Fagocitosis/inmunología , Inmunidad Adaptativa/inmunología , Animales , Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Células Cultivadas , Senescencia Celular/inmunología , Células Dendríticas/metabolismo , Células Dendríticas/trasplante , Ratones , Ratones Endogámicos C57BL , Mitocondrias/patología , Ovalbúmina/inmunología , Fosforilación Oxidativa , Especies Reactivas de Oxígeno/metabolismo
3.
Front Immunol ; 15: 1341804, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38515757

RESUMEN

IL-15 has shown preclinical activity by enhancing the functional maturation of natural killer (NK) cells. Clinical evaluation of the potential anticancer activity of most cytokines, including IL-15, has been limited by low tolerability and rapid in vivo clearance. Efbalropendekin Alfa (XmAb24306) is a soluble IL15/IL15-receptor alpha heterodimer complex fused to a half-life extended Fc domain (IL15/IL15Rα-Fc), engineered with mutations to reduce IL-15 affinity for CD122. Reduced affinity drives lower potency, leading to prolonged pharmacodynamic response in cynomolgus monkeys. We show that in vitro, human NK cells treated with XmAb24306 demonstrate enhanced cytotoxicity against various tumor cell lines. XmAb24306-treated NK cells also exhibit enhanced killing of 3D colorectal cancer spheroids. Daratumumab (dara), a monoclonal antibody (mAb) that targets CD38 results in antibody-dependent cellular cytotoxicity (ADCC) of both multiple myeloma (MM) cells and NK cells. Addition of XmAb24306 increases dara-mediated NK cell ADCC against various MM cell lines in vitro. Because NK cells express CD38, XmAb24306 increases dara-mediated NK cell fratricide, but overall does not negatively impact the ADCC activity against a MM cell line likely due to increased NK cell activity of the surviving cells. These data show that XmAb24306 increases direct and ADCC-mediated human NK cell cytotoxicity in vitro.


Asunto(s)
Antineoplásicos , Interleucina-15 , Humanos , Interleucina-15/farmacología , Interleucina-15/metabolismo , Antineoplásicos/farmacología , Citocinas/metabolismo , Factores Inmunológicos/metabolismo , Células Asesinas Naturales , Línea Celular Tumoral
4.
Cell Rep Med ; 5(2): 101393, 2024 Feb 20.
Artículo en Inglés | MEDLINE | ID: mdl-38280376

RESUMEN

In metastatic urothelial cancer (mUC), cisplatin versus carboplatin leads to durable disease control in a subset of patients. The IMvigor130 trial reveals more favorable effects with atezolizumab combined with gemcitabine and cisplatin (GemCis) versus gemcitabine and carboplatin (GemCarbo). This study investigates the immunomodulatory effects of cisplatin as a potential explanation for these observations. Our findings indicate that improved outcomes with GemCis versus GemCarbo are primarily observed in patients with pretreatment tumors exhibiting features of restrained adaptive immunity. In addition, GemCis versus GemCarbo ± atezolizumab induces transcriptional changes in circulating immune cells, including upregulation of antigen presentation and T cell activation programs. In vitro experiments demonstrate that cisplatin, compared with carboplatin, exerts direct immunomodulatory effects on cancer cells, promoting dendritic cell activation and antigen-specific T cell killing. These results underscore the key role of immune modulation in cisplatin's efficacy in mUC and highlight the importance of specific chemotherapy backbones in immunotherapy combination regimens.


Asunto(s)
Anticuerpos Monoclonales Humanizados , Carcinoma de Células Transicionales , Neoplasias de la Vejiga Urinaria , Neoplasias Urológicas , Humanos , Carboplatino/uso terapéutico , Carcinoma de Células Transicionales/tratamiento farmacológico , Carcinoma de Células Transicionales/inducido químicamente , Carcinoma de Células Transicionales/patología , Cisplatino/uso terapéutico , Desoxicitidina/uso terapéutico , Gemcitabina , Neoplasias de la Vejiga Urinaria/tratamiento farmacológico , Neoplasias de la Vejiga Urinaria/patología , Neoplasias Urológicas/tratamiento farmacológico , Neoplasias Urológicas/inducido químicamente , Neoplasias Urológicas/patología
5.
Nat Commun ; 10(1): 4344, 2019 09 25.
Artículo en Inglés | MEDLINE | ID: mdl-31554802

RESUMEN

Innate immune responses to Zika virus (ZIKV) are dampened in the lower female reproductive tract (LFRT) compared to other tissues, but the mechanism that underlies this vulnerability is poorly understood. Using tissues from uninfected and vaginally ZIKV-infected macaques and mice, we show that low basal expression of RNA-sensing pattern recognition receptors (PRRs), or their co-receptors, in the LFRT contributes to high viral replication in this tissue. In the LFRT, ZIKV sensing provides limited protection against viral replication, and the sensors are also minimally induced after vaginal infection. While IFNα/ß receptor signaling offers minimal protection in the LFRT, it is required to prevent dissemination of ZIKV to other tissues, including the upper FRT. Our findings support a role for RNA-sensing PRRs in the dampened innate immunity against ZIKV in the LFRT compared to other tissues and underlie potential implications for systemic dissemination upon heterosexual transmission of ZIKV in women.


Asunto(s)
Genitales Femeninos/inmunología , Inmunidad Innata/inmunología , ARN Viral/inmunología , Infección por el Virus Zika/inmunología , Virus Zika/inmunología , Animales , Femenino , Regulación Viral de la Expresión Génica , Genitales Femeninos/metabolismo , Genitales Femeninos/virología , Humanos , Inmunidad Innata/genética , Macaca mulatta , Ratones Endogámicos C57BL , Ratones Noqueados , ARN Viral/genética , Receptor de Interferón alfa y beta/genética , Receptor de Interferón alfa y beta/inmunología , Receptor de Interferón alfa y beta/metabolismo , Receptores de Reconocimiento de Patrones/genética , Receptores de Reconocimiento de Patrones/inmunología , Receptores de Reconocimiento de Patrones/metabolismo , Receptor Toll-Like 3/genética , Receptor Toll-Like 3/inmunología , Receptor Toll-Like 3/metabolismo , Vagina/inmunología , Vagina/metabolismo , Vagina/virología , Replicación Viral/genética , Replicación Viral/inmunología , Virus Zika/genética , Virus Zika/fisiología , Infección por el Virus Zika/genética , Infección por el Virus Zika/virología
6.
Cell Rep ; 28(8): 2169-2181.e4, 2019 08 20.
Artículo en Inglés | MEDLINE | ID: mdl-31433990

RESUMEN

Coordinate control of T cell proliferation, survival, and differentiation are essential for host protection from pathogens and cancer. Long-lived memory cells, whose precursors are formed during the initial immunological insult, provide protection from future encounters, and their generation is the goal of many vaccination strategies. microRNAs (miRNAs) are key nodes in regulatory networks that shape effective T cell responses through the fine-tuning of thousands of genes. Here, using compound conditional mutant mice to eliminate miR-15/16 family miRNAs in T cells, we show that miR-15/16 restrict T cell cycle, survival, and memory T cell differentiation. High throughput sequencing of RNA isolated by cross-linking immunoprecipitation of AGO2 combined with gene expression analysis in miR-15/16-deficient T cells indicates that these effects are mediated through the direct inhibition of an extensive network of target genes within pathways critical to cell cycle, survival, and memory.


Asunto(s)
Ciclo Celular , Diferenciación Celular , Memoria Inmunológica , MicroARNs/metabolismo , Linfocitos T/citología , Linfocitos T/inmunología , Animales , Antígenos/metabolismo , Ciclo Celular/genética , Diferenciación Celular/genética , Supervivencia Celular/genética , Regulación de la Expresión Génica , Redes Reguladoras de Genes , Sitios Genéticos , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Transgénicos , MicroARNs/genética
7.
Front Immunol ; 8: 1311, 2017.
Artículo en Inglés | MEDLINE | ID: mdl-29085369

RESUMEN

The realization that an intricate link exists between the metabolic state of immune cells and the nature of the elicited immune responses has brought a dramatic evolution to the field of immunology. We will focus on how metabolic reprogramming through the use of glycolysis and fatty-acid oxidation (sugar or fat) regulates the capacity of immune cells to mount robust and effective immune responses. We will also discuss how fine-tuning sugar and fat metabolism may be exploited as a novel immunotherapeutic strategy to fight viral infections or improve vaccine efficacy.

8.
Aging Cell ; 14(2): 191-9, 2015 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-25677698

RESUMEN

Natural killer (NK) cells are critical in eliminating tumors and viral infections, both of which occur at a high incidence in the elderly. Previous studies showed that aged NK cells are less cytotoxic and exhibit impaired maturation compared to young NK cells. We evaluated whether extrinsic or intrinsic factors were responsible for the impaired maturation and function of NK cells in aging and whether impaired maturation correlated with functional hyporesponsiveness. We confirmed that aged mice have a significant decrease in the frequency of mature NK cells in all lymphoid organs. Impaired NK cell maturation in aged mice correlated with a reduced capacity to eliminate allogeneic and B16 tumor targets in vivo. This could be explained by impaired degranulation, particularly by mature NK cells of aged mice. Consistent with impaired aged NK cell maturation, expression of T-bet and Eomes, which regulate NK cell functional maturation, was significantly decreased in aged bone marrow (BM) NK cells. Mixed BM chimeras revealed that the nonhematopoietic environment was a key determinant of NK cell maturation and T-bet and Eomes expression. In mixed BM chimeras, NK cells derived from both young or aged BM cells adopted an 'aged' phenotype in an aged host, that is, were hyporesponsive to stimuli in vitro, while adopting a 'young' phenotype following transfer in young hosts. Overall, our data suggest that the aged nonhematopoietic environment is responsible for the impaired maturation and function of NK cells. Defining these nonhematopoietic factors could have important implications for improving NK cell function in the elderly.


Asunto(s)
Senescencia Celular/inmunología , Células Asesinas Naturales/citología , Anciano , Animales , Diferenciación Celular/inmunología , Citocinas/inmunología , Femenino , Humanos , Células Asesinas Naturales/inmunología , Ratones , Ratones Endogámicos C57BL
9.
J Innate Immun ; 6(5): 685-94, 2014.
Artículo en Inglés | MEDLINE | ID: mdl-24861338

RESUMEN

Up to a third of the world's population is infected with Toxoplasma gondii. Natural infection in humans can be life threatening during pregnancy and in immunocompromised individuals. Toll-like receptor (TLR) 11 is the mouse innate sensor that recognizes T. gondii profilin; however, in humans the TLR11 gene leads to transcription of no functional protein. Herein, by using a multiple sequence alignment phylogenetic analysis program between human and mouse species, we found that human TLR5 seems to be the evolutionarily closest member of the TLR gene family to mouse tlr11. We therefore asked whether human TLR5 could mediate IL-6, IL-8 and IL-12p70 production in response to the T. gondii profilin. We found that this was the case both in human cell lines as well as peripheral blood monocytes. Moreover, TLR5 neutralization and gene silencing mediated specific ablation of cytokine production after profilin exposure. Finally, peripheral blood monocytes carrying the TLR5 R392X mutation failed to produce cytokines in response to stimulation with profilin. Taken together, the results presented herein reveal a previously unappreciated cross-recognition of a relevant human pathogen-derived pathogen-associated molecular pattern.


Asunto(s)
Monocitos/inmunología , Profilinas/inmunología , Proteínas Protozoarias/inmunología , Receptor Toll-Like 5/metabolismo , Toxoplasma/inmunología , Secuencia de Aminoácidos , Animales , Línea Celular , Citocinas/metabolismo , Interacciones Huésped-Patógeno , Humanos , Ratones , Datos de Secuencia Molecular , Mutación/genética , Filogenia , ARN Interferente Pequeño/genética , Alineación de Secuencia , Homología de Secuencia de Aminoácido , Receptor Toll-Like 5/genética , Receptores Toll-Like/genética , Transgenes/genética
10.
Curr Opin Immunol ; 24(4): 482-7, 2012 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-22560294

RESUMEN

A hallmark of aging is the progressive deterioration of immune function. Age-related immune suppression increases susceptibility to infectious diseases and cancer, significant causes of morbidity and mortality in the elderly. In particular, age-related T cell dysfunction is a major contributor to 'immune-senescence'. Recently, it has become clear that the frequency of regulatory T cells (Treg) significantly increases in aged mice and humans. As Treg control the intensity of T cell responses, their accrual probably contributes to age-related immune dysfunction. This review will focus on mechanisms underlying Treg homeostasis and function in aging.


Asunto(s)
Envejecimiento/fisiología , Homeostasis/fisiología , Linfocitos T Reguladores/inmunología , Animales , Humanos
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