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1.
Annu Rev Immunol ; 34: 265-97, 2016 05 20.
Artículo en Inglés | MEDLINE | ID: mdl-26907214

RESUMEN

MHC class II (MHC-II) molecules are critical in the control of many immune responses. They are also involved in most autoimmune diseases and other pathologies. Here, we describe the biology of MHC-II and MHC-II variations that affect immune responses. We discuss the classic cell biology of MHC-II and various perturbations. Proteolysis is a major process in the biology of MHC-II, and we describe the various components forming and controlling this endosomal proteolytic machinery. This process ultimately determines the MHC-II-presented peptidome, including cryptic peptides, modified peptides, and other peptides that are relevant in autoimmune responses. MHC-II also variable in expression, glycosylation, and turnover. We illustrate that MHC-II is variable not only in amino acids (polymorphic) but also in its biology, with consequences for both health and disease.


Asunto(s)
Presentación de Antígeno , Antígenos/metabolismo , Endosomas/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Enfermedades del Sistema Inmune/inmunología , Animales , Antígenos/inmunología , Autoinmunidad , Endocitosis , Regulación de la Expresión Génica , Glicosilación , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Fragmentos de Péptidos/inmunología , Polimorfismo Genético , Transporte de Proteínas , Proteolisis
2.
Annu Rev Immunol ; 33: 169-200, 2015.
Artículo en Inglés | MEDLINE | ID: mdl-25493333

RESUMEN

The Major Histocompatibility Complex (MHC) locus encodes classical MHC class I and MHC class II molecules and nonclassical MHC-I molecules. The architecture of these molecules is ideally suited to capture and present an array of peptide antigens (Ags). In addition, the CD1 family members and MR1 are MHC class I-like molecules that bind lipid-based Ags and vitamin B precursors, respectively. These Ag-bound molecules are subsequently recognized by T cell antigen receptors (TCRs) expressed on the surface of T lymphocytes. Structural and associated functional studies have been highly informative in providing insight into these interactions, which are crucial to immunity, and how they can lead to aberrant T cell reactivity. Investigators have determined over thirty unique TCR-peptide-MHC-I complex structures and twenty unique TCR-peptide-MHC-II complex structures. These investigations have shown a broad consensus in docking geometry and provided insight into MHC restriction. Structural studies on TCR-mediated recognition of lipid and metabolite Ags have been mostly confined to TCRs from innate-like natural killer T cells and mucosal-associated invariant T cells, respectively. These studies revealed clear differences between TCR-lipid-CD1, TCR-metabolite-MR1, and TCR-peptide-MHC recognition. Accordingly, TCRs show remarkable structural and biological versatility in engaging different classes of Ag that are presented by polymorphic and monomorphic Ag-presenting molecules of the immune system.


Asunto(s)
Presentación de Antígeno , Antígenos/inmunología , Antígenos/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Antígenos/química , Reacciones Cruzadas/inmunología , Antígenos de Histocompatibilidad Clase I/química , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase II/química , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Lípidos/inmunología , Unión Proteica/inmunología , Receptores de Antígenos de Linfocitos T/química
3.
Annu Rev Biochem ; 89: 717-739, 2020 06 20.
Artículo en Inglés | MEDLINE | ID: mdl-32569519

RESUMEN

In all human cells, human leukocyte antigen (HLA) class I glycoproteins assemble with a peptide and take it to the cell surface for surveillance by lymphocytes. These include natural killer (NK) cells and γδ T cells of innate immunity and αß T cells of adaptive immunity. In healthy cells, the presented peptides derive from human proteins, to which lymphocytes are tolerant. In pathogen-infected cells, HLA class I expression is perturbed. Reduced HLA class I expression is detected by KIR and CD94:NKG2A receptors of NK cells. Almost any change in peptide presentation can be detected by αß CD8+ T cells. In responding to extracellular pathogens, HLA class II glycoproteins, expressed by specialized antigen-presenting cells, present peptides to αß CD4+ T cells. In comparison to the families of major histocompatibility complex (MHC) class I, MHC class II and αß T cell receptors, the antigenic specificity of the γδ T cell receptors is incompletely understood.


Asunto(s)
Antígenos de Histocompatibilidad Clase II/química , Antígenos de Histocompatibilidad Clase I/química , Inmunidad Celular , Subfamília D de Receptores Similares a Lectina de las Células NK/química , Receptores de Antígenos de Linfocitos T alfa-beta/química , Receptores de Antígenos de Linfocitos T gamma-delta/química , Receptores KIR/química , Presentación de Antígeno , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Evolución Molecular , Regulación de la Expresión Génica , Haplotipos , Antígenos de Histocompatibilidad Clase I/clasificación , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase II/clasificación , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Inmunidad Innata , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Modelos Moleculares , Subfamília D de Receptores Similares a Lectina de las Células NK/genética , Subfamília D de Receptores Similares a Lectina de las Células NK/inmunología , Dominios y Motivos de Interacción de Proteínas , Estructura Secundaria de Proteína , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/genética , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores KIR/clasificación , Receptores KIR/genética , Receptores KIR/inmunología , Transducción de Señal
4.
Cell ; 182(6): 1441-1459.e21, 2020 09 17.
Artículo en Inglés | MEDLINE | ID: mdl-32888430

RESUMEN

Throughout a 24-h period, the small intestine (SI) is exposed to diurnally varying food- and microbiome-derived antigenic burdens but maintains a strict immune homeostasis, which when perturbed in genetically susceptible individuals, may lead to Crohn disease. Herein, we demonstrate that dietary content and rhythmicity regulate the diurnally shifting SI epithelial cell (SIEC) transcriptional landscape through modulation of the SI microbiome. We exemplify this concept with SIEC major histocompatibility complex (MHC) class II, which is diurnally modulated by distinct mucosal-adherent SI commensals, while supporting downstream diurnal activity of intra-epithelial IL-10+ lymphocytes regulating the SI barrier function. Disruption of this diurnally regulated diet-microbiome-MHC class II-IL-10-epithelial barrier axis by circadian clock disarrangement, alterations in feeding time or content, or epithelial-specific MHC class II depletion leads to an extensive microbial product influx, driving Crohn-like enteritis. Collectively, we highlight nutritional features that modulate SI microbiome, immunity, and barrier function and identify dietary, epithelial, and immune checkpoints along this axis to be potentially exploitable in future Crohn disease interventions.


Asunto(s)
Enfermedad de Crohn/microbiología , Células Epiteliales/metabolismo , Microbioma Gastrointestinal , Antígenos de Histocompatibilidad Clase II/metabolismo , Intestino Delgado/inmunología , Intestino Delgado/microbiología , Transcriptoma/genética , Animales , Antibacterianos/farmacología , Relojes Circadianos/fisiología , Enfermedad de Crohn/inmunología , Enfermedad de Crohn/metabolismo , Dieta , Células Epiteliales/citología , Células Epiteliales/inmunología , Citometría de Flujo , Microbioma Gastrointestinal/efectos de los fármacos , Microbioma Gastrointestinal/genética , Perfilación de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Homeostasis , Hibridación Fluorescente in Situ , Interleucina-10/metabolismo , Interleucina-10/farmacología , Intestino Delgado/fisiología , Linfocitos , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Periodicidad , Linfocitos T/inmunología , Transcriptoma/fisiología
5.
Cell ; 176(1-2): 334-347.e12, 2019 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-30580966

RESUMEN

Lymphocyte-activation gene 3 (LAG-3) is an immune inhibitory receptor, with major histocompatibility complex class II (MHC-II) as a canonical ligand. However, it remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3. Here, we demonstrate that fibrinogen-like protein 1 (FGL1), a liver-secreted protein, is a major LAG-3 functional ligand independent from MHC-II. FGL1 inhibits antigen-specific T cell activation, and ablation of FGL1 in mice promotes T cell immunity. Blockade of the FGL1-LAG-3 interaction by monoclonal antibodies stimulates tumor immunity and is therapeutic against established mouse tumors in a receptor-ligand inter-dependent manner. FGL1 is highly produced by human cancer cells, and elevated FGL1 in the plasma of cancer patients is associated with a poor prognosis and resistance to anti-PD-1/B7-H1 therapy. Our findings reveal an immune evasion mechanism and have implications for the design of cancer immunotherapy.


Asunto(s)
Antígenos CD/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Neoplasias/fisiología , Animales , Antígenos CD/inmunología , Línea Celular , Fibrinógeno/inmunología , Fibrinógeno/metabolismo , Genes MHC Clase II/genética , Genes MHC Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Inmunoterapia , Ligandos , Hígado/metabolismo , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteínas de Neoplasias/genética , Neoplasias/inmunología , Linfocitos T Citotóxicos/inmunología , Proteína del Gen 3 de Activación de Linfocitos
6.
Cell ; 175(2): 416-428.e13, 2018 10 04.
Artículo en Inglés | MEDLINE | ID: mdl-30245014

RESUMEN

The anti-cancer immune response against mutated peptides of potential immunological relevance (neoantigens) is primarily attributed to MHC-I-restricted cytotoxic CD8+ T cell responses. MHC-II-restricted CD4+ T cells also drive anti-tumor responses, but their relation to neoantigen selection and tumor evolution has not been systematically studied. Modeling the potential of an individual's MHC-II genotype to present 1,018 driver mutations in 5,942 tumors, we demonstrate that the MHC-II genotype constrains the mutational landscape during tumorigenesis in a manner complementary to MHC-I. Mutations poorly bound to MHC-II are positively selected during tumorigenesis, even more than mutations poorly bound to MHC-I. This emphasizes the importance of CD4+ T cells in anti-tumor immunity. In addition, we observed less inter-patient variation in mutation presentation for MHC-II than for MHC-I. These differences were reflected by age at diagnosis, which was correlated with presentation by MHC-I only. Collectively, our results emphasize the central role of MHC-II presentation in tumor evolution.


Asunto(s)
Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Neoplasias/genética , Factores de Edad , Animales , Antígenos de Neoplasias/inmunología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Evolución Molecular , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunoterapia/métodos , Mutación/genética
7.
Nat Immunol ; 20(7): 928-942, 2019 07.
Artículo en Inglés | MEDLINE | ID: mdl-31061532

RESUMEN

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.


Asunto(s)
Artritis Reumatoide/genética , Artritis Reumatoide/metabolismo , Perfilación de la Expresión Génica , Membrana Sinovial/metabolismo , Transcriptoma , Artritis Reumatoide/patología , Autoinmunidad/genética , Biomarcadores , Biología Computacional/métodos , Estudios Transversales , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometría de Flujo , Expresión Génica , Perfilación de la Expresión Génica/métodos , Secuenciación de Nucleótidos de Alto Rendimiento , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Humanos , Leucocitos/inmunología , Leucocitos/metabolismo , Monocitos/inmunología , Monocitos/metabolismo , Transducción de Señal , Análisis de la Célula Individual/métodos , Membrana Sinovial/patología , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Flujo de Trabajo
8.
Immunity ; 54(1): 116-131.e10, 2021 01 12.
Artículo en Inglés | MEDLINE | ID: mdl-33271120

RESUMEN

Tumors frequently subvert major histocompatibility complex class I (MHC-I) peptide presentation to evade CD8+ T cell immunosurveillance, though how this is accomplished is not always well defined. To identify the global regulatory networks controlling antigen presentation, we employed genome-wide screening in human diffuse large B cell lymphomas (DLBCLs). This approach revealed dozens of genes that positively and negatively modulate MHC-I cell surface expression. Validated genes clustered in multiple pathways including cytokine signaling, mRNA processing, endosomal trafficking, and protein metabolism. Genes can exhibit lymphoma subtype- or tumor-specific MHC-I regulation, and a majority of primary DLBCL tumors displayed genetic alterations in multiple regulators. We established SUGT1 as a major positive regulator of both MHC-I and MHC-II cell surface expression. Further, pharmacological inhibition of two negative regulators of antigen presentation, EZH2 and thymidylate synthase, enhanced DLBCL MHC-I presentation. These and other genes represent potential targets for manipulating MHC-I immunosurveillance in cancers, infectious diseases, and autoimmunity.


Asunto(s)
Linfocitos B/fisiología , Biomarcadores de Tumor/genética , Antígenos HLA/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase I/genética , Linfoma de Células B Grandes Difuso/genética , Carcinogénesis/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Diferenciación Celular , Línea Celular Tumoral , Linaje de la Célula , Proteína Potenciadora del Homólogo Zeste 2/genética , Proteína Potenciadora del Homólogo Zeste 2/metabolismo , Regulación Neoplásica de la Expresión Génica , Pruebas Genéticas , Estudio de Asociación del Genoma Completo , Antígenos HLA/metabolismo , Humanos , Vigilancia Inmunológica , Linfoma de Células B Grandes Difuso/metabolismo , Escape del Tumor/genética
9.
Immunity ; 53(5): 1001-1014.e20, 2020 11 17.
Artículo en Inglés | MEDLINE | ID: mdl-33022229

RESUMEN

The gut epithelium is populated by intraepithelial lymphocytes (IELs), a heterogeneous T cell population with cytotoxic and regulatory properties, which can be acquired at the epithelial layer. However, the role of T cell receptor (TCR) in this process remains unclear. Single-cell transcriptomic analyses revealed distinct clonal expansions between cell states, with CD4+CD8αα+ IELs being one of the least diverse populations. Conditional deletion of TCR on differentiating CD4+ T cells or of major histocompatibility complex (MHC) class II on intestinal epithelial cells prevented CD4+CD8αα+ IEL differentiation. However, TCR ablation on differentiated CD4+CD8αα+ IELs or long-term cognate antigen withdraw did not affect their maintenance. TCR re-engagement of antigen-specific CD4+CD8αα+ IELs by Listeria monocytogenes did not alter their state but correlated with reduced bacterial invasion. Thus, local antigen recognition is an essential signal for differentiation of CD4+ T cells at the epithelium, yet differentiated IELs are able to preserve an effector program in the absence of TCR signaling.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Mucosa Intestinal/inmunología , Mucosa Intestinal/metabolismo , Linfocitos Intraepiteliales/inmunología , Linfocitos Intraepiteliales/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Evolución Clonal/genética , Evolución Clonal/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/inmunología , Inmunofenotipificación , Ratones , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Transducción de Señal , Análisis de la Célula Individual , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo
10.
Immunity ; 51(4): 766-779.e17, 2019 10 15.
Artículo en Inglés | MEDLINE | ID: mdl-31495665

RESUMEN

Increasing evidence indicates CD4+ T cells can recognize cancer-specific antigens and control tumor growth. However, it remains difficult to predict the antigens that will be presented by human leukocyte antigen class II molecules (HLA-II), hindering efforts to optimally target them therapeutically. Obstacles include inaccurate peptide-binding prediction and unsolved complexities of the HLA-II pathway. To address these challenges, we developed an improved technology for discovering HLA-II binding motifs and conducted a comprehensive analysis of tumor ligandomes to learn processing rules relevant in the tumor microenvironment. We profiled >40 HLA-II alleles and showed that binding motifs were highly sensitive to HLA-DM, a peptide-loading chaperone. We also revealed that intratumoral HLA-II presentation was dominated by professional antigen-presenting cells (APCs) rather than cancer cells. Integrating these observations, we developed algorithms that accurately predicted APC ligandomes, including peptides from phagocytosed cancer cells. These tools and biological insights will enable improved HLA-II-directed cancer therapies.


Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Vacunas contra el Cáncer/inmunología , Mapeo Epitopo/métodos , Antígenos HLA/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Inmunoterapia/métodos , Espectrometría de Masas/métodos , Neoplasias/terapia , Algoritmos , Alelos , Presentación de Antígeno , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Conjuntos de Datos como Asunto , Antígenos HLA/genética , Antígenos HLA-D/metabolismo , Humanos , Neoplasias/inmunología , Unión Proteica , Dominios y Motivos de Interacción de Proteínas/genética , Programas Informáticos
11.
Immunity ; 51(5): 885-898.e7, 2019 11 19.
Artículo en Inglés | MEDLINE | ID: mdl-31542340

RESUMEN

Graft-versus-host disease (GVHD) in the gastrointestinal (GI) tract is the principal determinant of lethality following allogeneic bone marrow transplantation (BMT). Here, we examined the mechanisms that initiate GVHD, including the relevant antigen-presenting cells. MHC class II was expressed on intestinal epithelial cells (IECs) within the ileum at steady state but was absent from the IECs of germ-free mice. IEC-specific deletion of MHC class II prevented the initiation of lethal GVHD in the GI tract. MHC class II expression on IECs was absent from mice deficient in the TLR adaptors MyD88 and TRIF and required IFNγ secretion by lamina propria lymphocytes. IFNγ responses are characteristically driven by IL-12 secretion from myeloid cells. Antibiotic-mediated depletion of the microbiota inhibited IL-12/23p40 production by ileal macrophages. IL-12/23p40 neutralization prevented MHC class II upregulation on IECs and initiation of lethal GVHD in the GI tract. Thus, MHC class II expression by IECs in the ileum initiates lethal GVHD, and blockade of IL-12/23p40 may represent a readily translatable therapeutic strategy.


Asunto(s)
Presentación de Antígeno/inmunología , Células Presentadoras de Antígenos/inmunología , Microbioma Gastrointestinal/inmunología , Enfermedad Injerto contra Huésped/etiología , Antígenos de Histocompatibilidad Clase II/inmunología , Mucosa Intestinal/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Biomarcadores , Citocinas/metabolismo , Susceptibilidad a Enfermedades , Femenino , Expresión Génica , Enfermedad Injerto contra Huésped/mortalidad , Antígenos de Histocompatibilidad Clase II/genética , Íleon/metabolismo , Mucosa Intestinal/metabolismo , Mucosa Intestinal/microbiología , Estimación de Kaplan-Meier , Subgrupos Linfocitarios/inmunología , Subgrupos Linfocitarios/metabolismo , Masculino , Ratones , Ratones Transgénicos , Pronóstico , Regiones Promotoras Genéticas , Transducción de Señal
12.
Nat Immunol ; 16(11): 1153-61, 2015 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-26437244

RESUMEN

Central to adaptive immunity is the interaction between the αß T cell receptor (TCR) and peptide presented by the major histocompatibility complex (MHC) molecule. Presumably reflecting TCR-MHC bias and T cell signaling constraints, the TCR universally adopts a canonical polarity atop the MHC. We report the structures of two TCRs, derived from human induced T regulatory (iT(reg)) cells, complexed to an MHC class II molecule presenting a proinsulin-derived peptide. The ternary complexes revealed a 180° polarity reversal compared to all other TCR-peptide-MHC complex structures. Namely, the iT(reg) TCR α-chain and ß-chain are overlaid with the α-chain and ß-chain of MHC class II, respectively. Nevertheless, this TCR interaction elicited a peptide-reactive, MHC-restricted T cell signal. Thus TCRs are not 'hardwired' to interact with MHC molecules in a stereotypic manner to elicit a T cell signal, a finding that fundamentally challenges our understanding of TCR recognition.


Asunto(s)
Autoantígenos/metabolismo , Complejo Mayor de Histocompatibilidad/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Inmunidad Adaptativa , Presentación de Antígeno , Autoantígenos/química , Autoantígenos/genética , Células Cultivadas , Antígeno HLA-DR4/química , Antígeno HLA-DR4/genética , Antígeno HLA-DR4/metabolismo , Antígenos de Histocompatibilidad Clase II/química , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Humanos , Complejo Mayor de Histocompatibilidad/genética , Modelos Moleculares , Mutagénesis Sitio-Dirigida , Proinsulina/química , Proinsulina/genética , Proinsulina/inmunología , Dominios y Motivos de Interacción de Proteínas , Receptores de Antígenos de Linfocitos T/química , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T Reguladores/inmunología
13.
PLoS Genet ; 20(6): e1011309, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38885192

RESUMEN

PLK1 (Polo-like kinase 1) plays a critical role in the progression of lung adenocarcinoma (LUAD). Recent studies have unveiled that targeting PLK1 improves the efficacy of immunotherapy, highlighting its important role in the regulation of tumor immunity. Nevertheless, our understanding of the intricate interplay between PLK1 and the tumor microenvironment (TME) remains incomplete. Here, using genetically engineered mouse model and single-cell RNA-seq analysis, we report that PLK1 promotes an immunosuppressive TME in LUAD, characterized with enhanced M2 polarization of tumor associated macrophages (TAM) and dampened antigen presentation process. Mechanistically, elevated PLK1 coincides with increased secretion of CXCL2 cytokine, which promotes M2 polarization of TAM and diminishes expression of class II major histocompatibility complex (MHC-II) in professional antigen-presenting cells. Furthermore, PLK1 negatively regulates MHC-II expression in cancer cells, which has been shown to be associated with compromised tumor immunity and unfavorable patient outcomes. Taken together, our results reveal PLK1 as a novel modulator of TME in LUAD and provide possible therapeutic interventions.


Asunto(s)
Adenocarcinoma del Pulmón , Proteínas de Ciclo Celular , Neoplasias Pulmonares , Quinasa Tipo Polo 1 , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas , Análisis de la Célula Individual , Microambiente Tumoral , Animales , Humanos , Ratones , Adenocarcinoma del Pulmón/genética , Adenocarcinoma del Pulmón/inmunología , Adenocarcinoma del Pulmón/patología , Presentación de Antígeno/genética , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Línea Celular Tumoral , Quimiocina CXCL2/genética , Quimiocina CXCL2/metabolismo , Regulación Neoplásica de la Expresión Génica , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/inmunología , Neoplasias Pulmonares/patología , Proteínas Serina-Treonina Quinasas/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Proteínas Proto-Oncogénicas/genética , Proteínas Proto-Oncogénicas/metabolismo , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Macrófagos Asociados a Tumores/inmunología , Macrófagos Asociados a Tumores/metabolismo
14.
J Cell Sci ; 137(10)2024 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-38682259

RESUMEN

SARS-CoV-2 interferes with antigen presentation by downregulating major histocompatibility complex (MHC) II on antigen-presenting cells, but the mechanism mediating this process is unelucidated. Herein, analysis of protein and gene expression in human antigen-presenting cells reveals that MHC II is downregulated by the SARS-CoV-2 main protease, NSP5. This suppression of MHC II expression occurs via decreased expression of the MHC II regulatory protein CIITA. CIITA downregulation is independent of the proteolytic activity of NSP5, and rather, NSP5 delivers HDAC2 to the transcription factor IRF3 at an IRF-binding site within the CIITA promoter. Here, HDAC2 deacetylates and inactivates the CIITA promoter. This loss of CIITA expression prevents further expression of MHC II, with this suppression alleviated by ectopic expression of CIITA or knockdown of HDAC2. These results identify a mechanism by which SARS-CoV-2 limits MHC II expression, thereby delaying or weakening the subsequent adaptive immune response.


Asunto(s)
Antígenos de Histocompatibilidad Clase II , Histona Desacetilasa 2 , Proteínas Nucleares , Regiones Promotoras Genéticas , SARS-CoV-2 , Transactivadores , Humanos , Presentación de Antígeno/genética , Células Presentadoras de Antígenos/metabolismo , Células Presentadoras de Antígenos/inmunología , COVID-19/virología , COVID-19/inmunología , COVID-19/genética , COVID-19/metabolismo , Cisteína Endopeptidasas/metabolismo , Cisteína Endopeptidasas/genética , Regulación hacia Abajo/genética , Células HEK293 , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Histona Desacetilasa 2/metabolismo , Histona Desacetilasa 2/genética , Factor 3 Regulador del Interferón/metabolismo , Factor 3 Regulador del Interferón/genética , Proteínas Nucleares/metabolismo , Proteínas Nucleares/genética , Regiones Promotoras Genéticas/genética , SARS-CoV-2/genética , SARS-CoV-2/metabolismo , SARS-CoV-2/inmunología , Transactivadores/metabolismo , Transactivadores/genética , Proteínas no Estructurales Virales/metabolismo , Proteínas no Estructurales Virales/genética
15.
Nat Immunol ; 15(2): 161-7, 2014 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-24362890

RESUMEN

CD11b(+) dendritic cells (DCs) seem to be specialized for presenting antigens via major histocompatibility (MHC) class II complexes to stimulate helper T cells, but the genetic and regulatory basis for this is not established. Conditional deletion of Irf4 resulted in loss of CD11b(+) DCs, impaired formation of peptide-MHC class II complexes and defective priming of helper T cells but not of cytotoxic T lymphocyte (CTL) responses. Gene expression and chromatin immunoprecipitation followed by deep sequencing (ChIP-Seq) analyses delineated an IRF4-dependent regulatory module that programs enhanced MHC class II antigen presentation. Expression of the transcription factor IRF4 but not of IRF8 restored the ability of IRF4-deficient DCs to efficiently process and present antigen to MHC class II-restricted T cells and promote helper T cell responses. We propose that the evolutionary divergence of IRF4 and IRF8 facilitated the specialization of DC subsets for distinct modes of antigen presentation and priming of helper T cell versus CTL responses.


Asunto(s)
Presentación de Antígeno/genética , Células Dendríticas/inmunología , Antígenos de Histocompatibilidad Clase II/inmunología , Factores Reguladores del Interferón/metabolismo , Linfocitos T Citotóxicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Células Cultivadas , Perfilación de la Expresión Génica , Regulación de la Expresión Génica/genética , Regulación de la Expresión Génica/inmunología , Antígenos de Histocompatibilidad Clase II/genética , Factores Reguladores del Interferón/genética , Activación de Linfocitos/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica/genética , Transgenes/genética
16.
Nat Immunol ; 15(5): 439-448, 2014 May.
Artículo en Inglés | MEDLINE | ID: mdl-24681565

RESUMEN

Molecular mechanisms that maintain lineage integrity of helper T cells are largely unknown. Here we show histone deacetylases 1 and 2 (HDAC1 and HDAC2) as crucial regulators of this process. Loss of HDAC1 and HDAC2 during late T cell development led to the appearance of major histocompatibility complex (MHC) class II-selected CD4(+) helper T cells that expressed CD8-lineage genes such as Cd8a and Cd8b1. HDAC1 and HDAC2-deficient T helper type 0 (TH0) and TH1 cells further upregulated CD8-lineage genes and acquired a CD8(+) effector T cell program in a manner dependent on Runx-CBFß complexes, whereas TH2 cells repressed features of the CD8(+) lineage independently of HDAC1 and HDAC2. These results demonstrate that HDAC1 and HDAC2 maintain integrity of the CD4 lineage by repressing Runx-CBFß complexes that otherwise induce a CD8(+) effector T cell-like program in CD4(+) T cells.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Histona Desacetilasa 1/metabolismo , Histona Desacetilasa 2/metabolismo , Células TH1/inmunología , Animales , Diferenciación Celular/genética , Linaje de la Célula/genética , Células Cultivadas , Subunidades alfa del Factor de Unión al Sitio Principal/metabolismo , Subunidad beta del Factor de Unión al Sitio Principal/metabolismo , Citocinas/metabolismo , Citotoxicidad Inmunológica/genética , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Histona Desacetilasa 1/genética , Histona Desacetilasa 2/genética , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Unión Proteica
17.
Immunity ; 47(2): 310-322.e7, 2017 08 15.
Artículo en Inglés | MEDLINE | ID: mdl-28813660

RESUMEN

Select humans and animals control persistent viral infections via adaptive immune responses that include production of neutralizing antibodies. The precise genetic basis for the control remains enigmatic. Here, we report positional cloning of the gene responsible for production of retrovirus-neutralizing antibodies in mice of the I/LnJ strain. It encodes the beta subunit of the non-classical major histocompatibility complex class II (MHC-II)-like molecule H2-O, a negative regulator of antigen presentation. The recessive and functionally null I/LnJ H2-Ob allele supported the production of virus-neutralizing antibodies independently of the classical MHC haplotype. Subsequent bioinformatics and functional analyses of the human H2-Ob homolog, HLA-DOB, revealed both loss- and gain-of-function alleles, which could affect the ability of their carriers to control infections with human hepatitis B (HBV) and C (HCV) viruses. Thus, understanding of the previously unappreciated role of H2-O (HLA-DO) in immunity to infections may suggest new approaches in achieving neutralizing immunity to viruses.


Asunto(s)
Anticuerpos Neutralizantes , Antígenos HLA-D/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Inmunidad Humoral , Virus del Tumor Mamario del Ratón/inmunología , Virus Rauscher/inmunología , Infecciones por Retroviridae/inmunología , Animales , Anticuerpos Neutralizantes/metabolismo , Anticuerpos Antivirales/metabolismo , Presentación de Antígeno/genética , Biología Computacional , Femenino , Predisposición Genética a la Enfermedad , Antígenos HLA-D/genética , Células HeLa , Hepatitis B/inmunología , Hepatitis B/transmisión , Hepatitis C/inmunología , Hepatitis C/transmisión , Antígenos de Histocompatibilidad Clase II/genética , Humanos , Inmunidad Humoral/genética , Masculino , Ratones , Ratones Endogámicos , Ratones Noqueados , Mutación/genética , Polimorfismo Genético , Infecciones por Retroviridae/transmisión
18.
Proc Natl Acad Sci U S A ; 120(7): e2208509120, 2023 02 14.
Artículo en Inglés | MEDLINE | ID: mdl-36745791

RESUMEN

Antigenic peptides derived from introns are presented on major histocompatibility (MHC) class I molecules, but how these peptides are produced is poorly understood. Here, we show that an MHC class I epitope (SL8) sequence inserted in the second intron of the ß-globin gene in a C57BL/6 mouse (HBB) generates immune tolerance. Introduction of SL8-specific CD8+ T cells derived from OT-1 transgenic mice resulted in a threefold increase in OT-1 T cell proliferation in HBB animals, as compared to wild-type animals. The growth of MCA sarcoma cells expressing the intron-derived SL8 epitope was suppressed in wild-type animals compared to HBB mice. The ß-globin pre-mRNA was detected in the light polysomal fraction, and introducing stop codons identified a non-AUG initiation site between +228 and +255 nts upstream of the SL8. Isolation of ribosome footprints confirmed translation initiation within this 27 nt sequence. Furthermore, treatment with splicing inhibitor shifts the translation of the pre-mRNA to monosomal fractions and results in an increase of intron-derived peptide substrate as shown by polysome profiling and cell imaging. These results show that non-AUG-initiated translation of pre-mRNAs generates peptides for MHC class I immune tolerance and helps explain why alternative tissue-specific splicing is tolerated by the immune system.


Asunto(s)
Antígenos de Histocompatibilidad Clase I , Precursores del ARN , Animales , Ratones , Antígenos de Histocompatibilidad Clase I/genética , Precursores del ARN/genética , Linfocitos T CD8-positivos , Biosíntesis de Proteínas , Presentación de Antígeno , Ratones Endogámicos C57BL , Péptidos/metabolismo , Tolerancia Inmunológica/genética , Epítopos , Antígenos de Histocompatibilidad Clase II/genética
19.
Proc Natl Acad Sci U S A ; 120(24): e2218955120, 2023 06 13.
Artículo en Inglés | MEDLINE | ID: mdl-37279268

RESUMEN

Major histocompatibility complex (MHC) class I and II molecules play critical roles in the activation and regulation of adaptive immunity through antigen presentation to CD8+ and CD4+ T cells, respectively. Strict regulation of MHC expression is critical for proper immune responses. CIITA (MHC class II transactivator), an NLR (nucleotide-binding domain, leucine-rich-repeat containing) protein, is a master regulator of MHC class II (MHC-II) gene transcription. Although it has been known that CIITA activity is regulated at the transcriptional and protein levels, the mechanism to determine CIITA protein level has not been elucidated. Here, we show that FBXO11 is a bona fide E3 ligase of CIITA and regulates CIITA protein level through ubiquitination-mediated degradation. A nonbiased proteomic approach for CIITA-binding protein identified FBXO11, a member of the Skp1-Cullin-1-F-box E3 ligase complex, as a binding partner of CIITA but not MHC class I transactivator, NLRC5. The cycloheximide chase assay showed that the half-life of CIITA is mainly regulated by FBXO11 via the ubiquitin-proteasome system. The expression of FBXO11 led to the reduced MHC-II at the promoter activity level, transcriptional level, and surface expression level through downregulation of CIITA. Moreover, human and mouse FBXO11-deficient cells display increased levels of MHC-II and related genes. In normal and cancer tissues, FBXO11 expression level is negatively correlated with MHC-II. Interestingly, the expression of FBXO11, along with CIITA, is associated with prognosis of cancer patients. Therefore, FBXO11 is a critical regulator to determine the level of MHC-II, and its expression may serve as a biomarker for cancer.


Asunto(s)
Proteínas F-Box , Neoplasias , Animales , Humanos , Ratones , Proteínas F-Box/genética , Genes MHC Clase II , Antígenos de Histocompatibilidad Clase I/genética , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Antígenos HLA , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Neoplasias/genética , Proteína-Arginina N-Metiltransferasas/genética , Proteína-Arginina N-Metiltransferasas/metabolismo , Proteómica , Transactivadores/metabolismo , Ubiquitina/metabolismo , Ubiquitina-Proteína Ligasas/genética , Ubiquitina-Proteína Ligasas/metabolismo
20.
J Pathol ; 264(3): 250-269, 2024 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-39161125

RESUMEN

Testicular tumors represent the most common malignancy among young men. Nevertheless, the pathogenesis and molecular underpinning of testicular tumors remain largely elusive. We aimed to delineate the intricate intra-tumoral heterogeneity and the network of intercellular communication within the tumor microenvironment. A total of 40,760 single-cell transcriptomes were analyzed, encompassing samples from six individuals with seminomas, two patients with mixed germ cell tumors, one patient with a Leydig cell tumor, and three healthy donors. Five distinct malignant subclusters were identified in the constructed landscape. Among them, malignant 1 and 3 subclusters were associated with a more immunosuppressive state and displayed worse disease-free survival. Further analysis identified that APP-CD74 interactions were significantly strengthened between malignant 1 and 3 subclusters and 14 types of immune subpopulations. In addition, we established an aberrant spermatogenesis trajectory and delineated the global gene alterations of somatic cells in seminoma testes. Sertoli cells were identified as the somatic cell type that differed the most from healthy donors to seminoma testes. Cellular communication between spermatogonial stem cells and Sertoli cells is disturbed in seminoma testes. Our study delineates the intra-tumoral heterogeneity and the tumor immune microenvironment in testicular tumors, offering novel insights for targeted therapy. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.


Asunto(s)
Perfilación de la Expresión Génica , Análisis de la Célula Individual , Neoplasias Testiculares , Microambiente Tumoral , Humanos , Masculino , Neoplasias Testiculares/genética , Neoplasias Testiculares/patología , Neoplasias Testiculares/inmunología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Perfilación de la Expresión Génica/métodos , Antígenos de Histocompatibilidad Clase II/genética , Antígenos de Histocompatibilidad Clase II/metabolismo , Transcriptoma , Progresión de la Enfermedad , Regulación Neoplásica de la Expresión Génica , Seminoma/genética , Seminoma/patología , Seminoma/inmunología , Tolerancia Inmunológica/genética , Neoplasias de Células Germinales y Embrionarias/genética , Neoplasias de Células Germinales y Embrionarias/patología , Neoplasias de Células Germinales y Embrionarias/inmunología , Antígenos de Diferenciación de Linfocitos B
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