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1.
Nat Immunol ; 22(12): 1524-1537, 2021 12.
Artículo en Inglés | MEDLINE | ID: mdl-34795443

RESUMEN

Inhibiting PD-1:PD-L1 signaling has transformed therapeutic immune restoration. CD4+ T cells sustain immunity in chronic infections and cancer, yet little is known about how PD-1 signaling modulates CD4+ helper T (TH) cell responses or the ability to restore CD4+ TH-mediated immunity by checkpoint blockade. We demonstrate that PD-1:PD-L1 specifically suppressed CD4+ TH1 cell amplification, prevents CD4+ TH1 cytokine production and abolishes CD4+ cytotoxic killing capacity during chronic infection in mice. Inhibiting PD-L1 rapidly restored these functions, while simultaneously amplifying and activating TH1-like T regulatory cells, demonstrating a system-wide CD4-TH1 recalibration. This effect coincided with decreased T cell antigen receptor signaling, and re-directed type I interferon (IFN) signaling networks towards dominant IFN-γ-mediated responses. Mechanistically, PD-L1 blockade specifically targeted defined populations with pre-established, but actively suppressed proliferative potential, with limited impact on minimally cycling TCF-1+ follicular helper T cells, despite high PD-1 expression. Thus, CD4+ T cells require unique differentiation and functional states to be targets of PD-L1-directed suppression and therapeutic restoration.


Asunto(s)
Antígeno B7-H1/antagonistas & inhibidores , Inhibidores de Puntos de Control Inmunológico/farmacología , Activación de Linfocitos/efectos de los fármacos , Coriomeningitis Linfocítica/tratamiento farmacológico , Virus de la Coriomeningitis Linfocítica/inmunología , Células TH1/efectos de los fármacos , Traslado Adoptivo , Animales , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proliferación Celular/efectos de los fármacos , Enfermedad Crónica , Citocinas/metabolismo , Citotoxicidad Inmunológica/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Redes Reguladoras de Genes , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/metabolismo , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/patogenicidad , Ratones Endogámicos C57BL , Fenotipo , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Células TH1/inmunología , Células TH1/metabolismo , Células TH1/virología , Transcriptoma
2.
Immunity ; 54(3): 526-541.e7, 2021 03 09.
Artículo en Inglés | MEDLINE | ID: mdl-33515487

RESUMEN

Chronic viral infections increase severity of Mycobacterium tuberculosis (Mtb) coinfection. Here, we examined how chronic viral infections alter the pulmonary microenvironment to foster coinfection and worsen disease severity. We developed a coordinated system of chronic virus and Mtb infection that induced central clinical manifestations of coinfection, including increased Mtb burden, extra-pulmonary dissemination, and heightened mortality. These disease states were not due to chronic virus-induced immunosuppression or exhaustion; rather, increased amounts of the cytokine TNFα initially arrested pulmonary Mtb growth, impeding dendritic cell mediated antigen transportation to the lymph node and subverting immune-surveillance, allowing bacterial sanctuary. The cryptic Mtb replication delayed CD4 T cell priming, redirecting T helper (Th) 1 toward Th17 differentiation and increasing pulmonary neutrophilia, which diminished long-term survival. Temporally restoring CD4 T cell induction overcame these diverse disease sequelae to enhance Mtb control. Thus, Mtb co-opts TNFα from the chronic inflammatory environment to subvert immune-surveillance, avert early immune function, and foster long-term coinfection.


Asunto(s)
Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/fisiología , Mycobacterium tuberculosis/fisiología , Neutrófilos/inmunología , Células TH1/inmunología , Células Th17/inmunología , Tuberculosis/inmunología , Inmunidad Adaptativa , Animales , Enfermedad Crónica , Coinfección , Inmunidad Innata , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Fagocitosis , Índice de Severidad de la Enfermedad , Factores de Tiempo
3.
Immunity ; 49(4): 678-694.e5, 2018 10 16.
Artículo en Inglés | MEDLINE | ID: mdl-30314757

RESUMEN

CD8+ T cell exhaustion impedes control of chronic viral infection; yet how new T cell responses are mounted during chronic infection is unclear. Unlike T cells primed at the onset of infection that rapidly differentiate into effectors and exhaust, we demonstrate that virus-specific CD8+ T cells primed after establishment of chronic LCMV infection preferentially generate memory-like transcription factor TCF1+ cells that were transcriptionally and proteomically distinct, less exhausted, and more responsive to immunotherapy. Mechanistically, adaptations of antigen-presenting cells and diminished T cell signaling intensity promoted differentiation of the memory-like subset at the expense of rapid effector cell differentiation, which was now highly dependent on IL-21-mediated CD4+ T cell help for its functional generation. Chronic viral infection similarly redirected de novo differentiation of tumor-specific CD8+ T cells, ultimately preventing cancer control. Thus, targeting these T cell stimulatory pathways could enable strategies to control chronic infection, tumors, and enhance immunotherapeutic efficacy.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Diferenciación Celular/inmunología , Inmunidad/inmunología , Memoria Inmunológica/inmunología , Coriomeningitis Linfocítica/inmunología , Virus de la Coriomeningitis Linfocítica/inmunología , Animales , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/virología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/virología , Diferenciación Celular/genética , Enfermedad Crónica , Perfilación de la Expresión Génica/métodos , Inmunidad/genética , Memoria Inmunológica/genética , Inmunoterapia , Coriomeningitis Linfocítica/terapia , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Ratones Endogámicos C57BL , Proteómica/métodos , Factor 1 de Transcripción de Linfocitos T/genética , Factor 1 de Transcripción de Linfocitos T/inmunología , Factor 1 de Transcripción de Linfocitos T/metabolismo
4.
J Immunol ; 195(10): 4892-9, 2015 Nov 15.
Artículo en Inglés | MEDLINE | ID: mdl-26453747

RESUMEN

The ability of CD4 T cells to give rise to specialized T follicular helper cells (TFH) critical to initiating appropriate Ab responses is regulated by environmental cues in lymphoid tissues draining the site of infection. In this study, we used a skin infection with HSV-1 characterized by the successive involvement of interconnected but distinct lymph nodes (LNs), to investigate the anatomical diversification of virus-specific CD4 T cell responses and the migratory capacity of TFH or their precursors. Whereas Th1 effector CD4 T cells expressing peripheral-targeting migration molecules readily migrated from primary to secondary reactive LNs, Bcl6(+) CXCR5(+) PD1(hi) TFH were largely retained at the site of initial activation with little spillover into the downstream LNs involved at later stages of infection. Consistent with this, TFH maintained high-level surface expression of CD69, indicative of impaired migratory capacity. Notably, the biased generation and retention of TFH in primary LNs correlated with a preferential generation of germinal centers at this site. Our results highlight a limited anatomical diversification of TFH responses and germinal center reactions that were imprinted within the first few cell divisions during TFH differentiation in LNs draining the site of initial infection.


Asunto(s)
Diferenciación Celular/inmunología , Movimiento Celular/inmunología , Centro Germinal/inmunología , Herpes Simple/inmunología , Herpesvirus Humano 1/inmunología , Células TH1/inmunología , Animales , Antígenos CD/genética , Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos de Diferenciación de Linfocitos T/inmunología , Diferenciación Celular/genética , Movimiento Celular/genética , Proteínas de Unión al ADN/genética , Proteínas de Unión al ADN/inmunología , Centro Germinal/patología , Herpes Simple/genética , Herpes Simple/patología , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Ratones , Ratones Transgénicos , Proteínas Proto-Oncogénicas c-bcl-6 , Receptores CXCR5/genética , Receptores CXCR5/inmunología , Células TH1/patología
5.
J Immunol ; 194(5): 2059-63, 2015 Mar 01.
Artículo en Inglés | MEDLINE | ID: mdl-25624457

RESUMEN

Tissue-resident memory T cells provide local immune protection in barrier tissues, such as skin and mucosa. However, the molecular mechanisms controlling effector T cell retention and subsequent memory formation in those locations are not fully understood. In this study, we analyzed the role of CD69, an early leukocyte activation marker, in regulating effector T cell egress from peripheral tissues. We provide evidence that CD69 surface expression by skin-infiltrating CD8 T cells can be regulated at multiple levels, including local Ag stimulation and signaling through type I IFNRs, and it coincides with the transcriptional downregulation of the sphingosine-1-phosphate receptor S1P1. Importantly, we demonstrate that expression of CD69, by interfering with sphingosine-1-phosphate receptor function, is a critical determinant of prolonged T cell retention and local memory formation. Our results define an important step in the generation of long-lived adaptive immune memory at body surfaces.


Asunto(s)
Antígenos CD/inmunología , Antígenos de Diferenciación de Linfocitos T/inmunología , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/inmunología , Memoria Inmunológica , Lectinas Tipo C/inmunología , Receptores de Lisoesfingolípidos/inmunología , Inmunidad Adaptativa , Animales , Antígenos CD/genética , Antígenos de Diferenciación de Linfocitos T/genética , Antígenos Virales/genética , Linfocitos T CD8-positivos/patología , Linfocitos T CD8-positivos/virología , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/patología , Células Dendríticas/virología , Femenino , Regulación de la Expresión Génica , Herpesvirus Humano 1/genética , Herpesvirus Humano 1/inmunología , Inmunofenotipificación , Interferón Tipo I/genética , Interferón Tipo I/inmunología , Lectinas Tipo C/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores de Lisoesfingolípidos/genética , Transducción de Señal , Piel/inmunología , Piel/patología , Piel/virología
6.
PLoS Pathog ; 10(8): e1004303, 2014 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25121482

RESUMEN

Efficient infection control requires potent T-cell responses at sites of pathogen replication. However, the regulation of T-cell effector function in situ remains poorly understood. Here, we show key differences in the regulation of effector activity between CD4+ and CD8+ T-cells during skin infection with HSV-1. IFN-γ-producing CD4+ T cells disseminated widely throughout the skin and draining lymph nodes (LN), clearly exceeding the epithelial distribution of infectious virus. By contrast, IFN-γ-producing CD8+ T cells were only found within the infected epidermal layer of the skin and associated hair follicles. Mechanistically, while various subsets of lymphoid- and skin-derived dendritic cells (DC) elicited IFN-γ production by CD4+ T cells, CD8+ T cells responded exclusively to infected epidermal cells directly presenting viral antigen. Notably, uninfected cross-presenting DCs from both skin and LNs failed to trigger IFN-γ production by CD8+ T-cells. Thus, we describe a previously unappreciated complexity in the regulation of CD4+ and CD8+ T-cell effector activity that is subset-specific, microanatomically distinct and involves largely non-overlapping types of antigen-presenting cells (APC).


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Herpes Simple/inmunología , Enfermedades Cutáneas Infecciosas/inmunología , Traslado Adoptivo , Animales , Modelos Animales de Enfermedad , Citometría de Flujo , Técnica del Anticuerpo Fluorescente , Herpesvirus Humano 1/inmunología , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Microscopía Confocal
7.
J Exp Med ; 217(12)2020 12 07.
Artículo en Inglés | MEDLINE | ID: mdl-32880629

RESUMEN

Many pathogens subvert intestinal immunity to persist within the gastrointestinal tract (GIT); yet, the underlying mechanisms that enable sanctuary specifically in this reservoir are unclear. Using mass cytometry and network analysis, we demonstrate that chronic LCMV infection of the GIT leads to dysregulated microbial composition, a cascade of metabolic alterations, increased susceptibility to GI disease, and a system-wide recalibration of immune composition that defines viral persistence. Chronic infection led to outgrowth of activated Tbet-expressing T reg cell populations unique to the GIT and the rapid erosion of pathogen-specific CD8 tissue-resident memory T cells. Mechanistically, T reg cells and coinhibitory receptors maintained long-term viral sanctuary within the GIT, and their targeting reactivated T cells and eliminated this viral reservoir. Thus, our data provide a high-dimensional definition of the mechanisms of immune regulation that chronic viruses implement to exploit the unique microenvironment of the GIT and identify T reg cells as key modulators of viral persistence in the intestinal tract.


Asunto(s)
Tracto Gastrointestinal/inmunología , Tracto Gastrointestinal/virología , Coriomeningitis Linfocítica/inmunología , Coriomeningitis Linfocítica/virología , Virus de la Coriomeningitis Linfocítica/fisiología , Animales , Efecto Espectador , Linfocitos T CD8-positivos/inmunología , Enfermedad Crónica , Colitis/complicaciones , Colitis/virología , Disbiosis/complicaciones , Disbiosis/virología , Tracto Gastrointestinal/microbiología , Tracto Gastrointestinal/patología , Regulación de la Expresión Génica , Activación de Linfocitos/inmunología , Depleción Linfocítica , Coriomeningitis Linfocítica/genética , Ratones Endogámicos C57BL , Fenotipo , Linfocitos T Reguladores/inmunología , Transcriptoma/genética
8.
Front Oncol ; 9: 415, 2019.
Artículo en Inglés | MEDLINE | ID: mdl-31165047

RESUMEN

Flow cytometry is a widely applied approach for exploratory immune profiling and biomarker discovery in cancer and other diseases. However, flow cytometry is limited by the number of parameters that can be simultaneously analyzed, severely restricting its utility. Recently, the advent of mass cytometry (CyTOF) has enabled high dimensional and unbiased examination of the immune system, allowing simultaneous interrogation of a large number of parameters. This is important for deep interrogation of immune responses and particularly when sample sizes are limited (such as in tumors). Our goal was to compare the accuracy and reproducibility of CyTOF against flow cytometry as a reliable analytic tool for human PBMC and tumor tissues for cancer clinical trials. We developed a 40+ parameter CyTOF panel and demonstrate that compared to flow cytometry, CyTOF yields analogous quantification of cell lineages in conjunction with markers of cell differentiation, function, activation, and exhaustion for use with fresh and viably frozen PBMC or tumor tissues. Further, we provide a protocol that enables reliable quantification by CyTOF down to low numbers of input human cells, an approach that is particularly important when cell numbers are limiting. Thus, we validate CyTOF as an accurate approach to perform high dimensional analysis in human tumor tissue and to utilize low cell numbers for subsequent immunologic studies and cancer clinical trials.

9.
Sci Immunol ; 4(42)2019 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-31836669

RESUMEN

General control nonderepressible 2 (GCN2) is an environmental sensor controlling transcription and translation in response to nutrient availability. Although GCN2 is a putative therapeutic target for immuno-oncology, its role in shaping the immune response to tumors is poorly understood. Here, we used mass cytometry, transcriptomics, and transcription factor-binding analysis to determine the functional impact of GCN2 on the myeloid phenotype and immune responses in melanoma. We found that myeloid-lineage deletion of GCN2 drives a shift in the phenotype of tumor-associated macrophages and myeloid-derived suppressor cells (MDSCs) that promotes antitumor immunity. Time-of-flight mass cytometry (CyTOF) and single-cell RNA sequencing showed that this was due to changes in the immune microenvironment with increased proinflammatory activation of macrophages and MDSCs and interferon-γ expression in intratumoral CD8+ T cells. Mechanistically, GCN2 altered myeloid function by promoting increased translation of the transcription factor CREB-2/ATF4, which was required for maturation and polarization of macrophages and MDSCs in both mice and humans, whereas targeting Atf4 by small interfering RNA knockdown reduced tumor growth. Last, analysis of patients with cutaneous melanoma showed that GCN2-dependent transcriptional signatures correlated with macrophage polarization, T cell infiltrates, and overall survival. Thus, these data reveal a previously unknown dependence of tumors on myeloid GCN2 signals for protection from immune attack.


Asunto(s)
Linfocitos T CD8-positivos/inmunología , Macrófagos/inmunología , Melanoma/inmunología , Células Supresoras de Origen Mieloide/inmunología , Proteínas Serina-Treonina Quinasas/inmunología , Microambiente Tumoral/inmunología , Animales , Células Cultivadas , Humanos , Ratones
10.
Nat Commun ; 7: 11514, 2016 05 10.
Artículo en Inglés | MEDLINE | ID: mdl-27160938

RESUMEN

Although memory T cells within barrier tissues can persist as permanent residents, at least some exchange with blood. The extent to which this occurs is unclear. Here we show that memory CD4(+) T cells in mouse skin are in equilibrium with the circulation at steady state. These cells are dispersed throughout the inter-follicular regions of the dermis and form clusters with antigen presenting cells around hair follicles. After infection or administration of a contact sensitizing agent, there is a sustained increase in skin CD4(+) T-cell content, which is confined to the clusters, with a concomitant CCL5-dependent increase in CD4(+) T-cell recruitment. Skin CCL5 is derived from CD11b(+) cells and CD8(+) T cells, with the elimination of the latter decreasing CD4(+) T-cell numbers. These results reveal a complex pattern of tissue-retention and equilibration for CD4(+) memory T cells in skin, which is altered by infection and inflammation history.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Adolescente , Adulto , Animales , Células Presentadoras de Antígenos/citología , Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/citología , Linfocitos T CD8-positivos/inmunología , Agregación Celular/inmunología , Movimiento Celular/inmunología , Quimiocina CCL5/metabolismo , Femenino , Folículo Piloso/citología , Folículo Piloso/inmunología , Herpes Simple/inmunología , Herpes Simple/patología , Herpesvirus Humano 1 , Humanos , Interferón gamma/biosíntesis , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Ratones Transgénicos , Persona de Mediana Edad , Piel/citología , Piel/inmunología , Adulto Joven
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