RESUMEN
CD1 isoforms are MHC class I-like molecules that present lipid-antigens to T cells and have been associated with a variety of immune responses. The lipid repertoire bound and presented by the four CD1 isoforms may be influenced by factors such as the cellular lipidome, subcellular microenvironment, and the properties of the binding pocket. In this study, by shotgun mass spectrometry, we performed a comprehensive lipidomic analysis of soluble CD1 molecules. We identified 1040 lipids, of which 293 were present in all isoforms. Comparative analysis revealed that the isoforms bind almost any cellular lipid.CD1a and CD1c closely mirrored the cellular lipidome, while CD1b and CD1d showed a preference for sphingolipids. Each CD1 isoform was found to have unique lipid species, suggesting some distinct roles in lipid presentation and immune responses. These findings contribute to our understanding of the role of CD1 system in immunity and could have implications for the development of lipid-based therapeutics.
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Antígenos CD1 , Lipidómica , Antígenos CD1/metabolismo , Antígenos CD1/inmunología , Humanos , Presentación de Antígeno/inmunología , Lípidos/inmunología , Metabolismo de los Lípidos , Isoformas de Proteínas/inmunología , Antígenos CD1d/metabolismo , Antígenos CD1d/inmunologíaRESUMEN
Introduction: Immunogenicity, the unwanted immune response triggered by therapeutic antibodies, poses significant challenges in biotherapeutic development. This response can lead to the production of anti-drug antibodies, potentially compromising the efficacy and safety of treatments. The internalization of therapeutic antibodies into dendritic cells (DCs) is a critical factor influencing immunogenicity. Using monoclonal antibodies, with differences in non-specific cellular uptake, as tools to explore the impact on the overall risk of immunogenicity, this study explores how internalization influences peptide presentation and subsequently T cell activation. Materials and methods: To investigate the impact of antibody internalization on immunogenicity, untargeted toolantibodies with engineered positive or negative charge patches were utilized. Immature monocyte-derived DCs (moDCs), known for their physiologically relevant high endocytic activity, were employed for internalization assays, while mature moDCs were used for MHC-II associated peptide proteomics (MAPPs) assays. In addition to the lysosomal accumulation and peptide presentation, subsequent CD4+ T cell activation has been assessed. Consequently, a known CD4+ T cell epitope from ovalbumin was inserted into the tool antibodies to evaluate T cell activation on a single, shared epitope. Results: Antibodies with positive charge patches exhibited higher rates of lysosomal accumulation and epitope presentation compared to those with negative charge patches or neutral surface charge. Furthermore, a direct correlation between internalization rate and presentation on MHC-II molecules could be established. To explore the link between internalization, peptide presentation and CD4+ T cell activation, tool antibodies containing the same OVA epitope were used. Previous observations were not altered by the insertion of the OVA epitope and ultimately, an enhanced CD4+ T cell response correlated with increased internalization in DCs and peptide presentation. Discussion: These findings demonstrate that the biophysical properties of therapeutic antibodies, particularly surface charge, play a crucial role in their internalization into DCs. Antibodies internalized faster and processed by DCs, are also more prone to be presented on their surface leading to a higher risk of triggering an immune response. These insights underscore the importance of considering antibody surface charge and other properties that enhance cellular accumulation during the preclinical development of biotherapeutics to mitigate immunogenicity risks.
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Presentación de Antígeno , Células Dendríticas , Activación de Linfocitos , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Humanos , Presentación de Antígeno/inmunología , Activación de Linfocitos/inmunología , Anticuerpos Monoclonales/inmunología , Linfocitos T CD4-Positivos/inmunología , Epítopos de Linfocito T/inmunología , Factores de Riesgo , Endocitosis/inmunología , Ovalbúmina/inmunologíaRESUMEN
Background: Defective ribosomal products (DRiPs) are non-functional proteins rapidly degraded during or after translation being an essential source for MHC class I ligands. DRiPs are characterized to derive from a substantial subset of nascent gene products that degrade more rapidly than their corresponding native retiree pool. So far, mass spectrometry analysis revealed that a large number of HLA class I peptides derive from DRiPs. However, a specific viral DRiP on protein level was not described. In this study, we aimed to characterize and identify DRiPs derived from a viral protein. Methods: Using the nucleoprotein (NP) of the lymphocytic choriomeningitis virus (LCMV) which is conjugated N-terminally to ubiquitin, or the ubiquitin-like modifiers FAT10 or ISG15 the occurrence of DRiPs was studied. The formation and degradation of DRiPs was monitored by western blot with the help of a FLAG tag. Flow cytometry and cytotoxic T cells were used to study antigen presentation. Results: We identified several short lived DRiPs derived from LCMV-NP. Of note, these DRiPs could only be observed when the LCMV-NP was modified with ubiquitin or ubiquitin-like modifiers, but not in the wild type form. Using proteasome inhibitors, we could show that degradation of LCMV-NP derived DRiPs were proteasome dependent. Interestingly, the synthesis of DRiPs could be enhanced when cells were stressed with the help of FCS starvation. An enhanced NP118-126 presentation was observed when the LCMV-NP was modified with ubiquitin or ubiquitin-like modifiers, or under FCS starvation. Conclusion: Taken together, we visualize for the first time DRiPs derived from a viral protein. Furthermore, DRiPs formation, and therefore MHC-I presentation, is enhanced under cellular stress conditions. Our investigations on DRiPs in MHC class I antigen presentation open up new approaches for the development of vaccination strategies.
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Presentación de Antígeno , Antígenos de Histocompatibilidad Clase I , Virus de la Coriomeningitis Linfocítica , Presentación de Antígeno/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Virus de la Coriomeningitis Linfocítica/inmunología , Animales , Humanos , Estrés Fisiológico/inmunología , Linfocitos T Citotóxicos/inmunología , Ratones , Ubiquitinas/metabolismo , Ubiquitinas/genética , Proteínas Ribosómicas/metabolismo , Proteínas Ribosómicas/inmunología , Proteolisis , Nucleoproteínas/inmunología , Nucleoproteínas/metabolismoRESUMEN
BACKGROUND: The antigen processing machinery (APM) plays a critical role in generating tumor-specific antigens that can be recognized and targeted by the immune system. Proper functioning of APM components is essential for presenting these antigens on the surface of tumor cells, enabling immune detection and destruction. In many cancers, defects in APM can lead to immune evasion, contributing to tumor progression and poor clinical outcomes. However, the status of the APM in sarcomas is not well characterized, limiting the development of effective immunotherapeutic strategies for these patients. METHODS: We investigated 126 patients with 8 types of bone and soft tissue sarcoma operated between 2001-2021. Tissue microarrays mapped 11 specific areas in each case. The presence/absence of APM protein was determined through immunohistochemistry. Bayesian networks were used. RESULTS: All investigated sarcomas had some defects in APM. The least damaged component was HLA Class I subunit ß2-microglobulin and HLA Class II. The proteasome LMP10 subunit was defective in leiomyosarcoma (LMS), myxoid liposarcoma (MLPS), and dedifferentiated liposarcoma (DDLPS), while MHC I transporting unit TAP2 was altered in undifferentiated pleomorphic sarcoma (UPS), gastrointestinal stromal tumor (GIST), and chordoma (CH). Among different neoplastic areas, high-grade areas showed different patterns of expression compared to high lymphocytic infiltrate areas. Heterogeneity at the patient level was also observed. Loss of any APM component was prognostic of distant metastasis (DM) for LMS and DDLPS and of overall survival (OS) for LMS. CONCLUSION: Sarcomas exhibit a high degree of defects in APM components, with differences among histotypes and tumoral areas. The most commonly altered APM components were HLA Class I subunit ß2-microglobulin, HLA Class I subunit α (HC10), and MHC I transporting unit TAP2. The loss of APM components was prognostic of DM and OS and clinically relevant for LMS and DDLPS. This study explores sarcoma molecular mechanisms, enriching personalized therapeutic approaches.
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Presentación de Antígeno , Sarcoma , Humanos , Sarcoma/inmunología , Sarcoma/patología , Presentación de Antígeno/inmunología , Masculino , Femenino , Persona de Mediana Edad , Anciano , Adulto , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Complejo de la Endopetidasa Proteasomal/metabolismo , Microglobulina beta-2/metabolismo , Pronóstico , Miembro 3 de la Subfamilia B de Transportadores de Casetes de Unión a ATPRESUMEN
Autoimmune diabetes is a disease characterized by the selective destruction of insulin-secreting ß-cells of the endocrine pancreas by islet-reactive T cells. Autoimmune disease requires a complex interplay between host genetic factors and environmental triggers that promote the activation of such antigen-specific T lymphocyte responses. Given the critical involvement of self-reactive T lymphocyte in diabetes pathogenesis, understanding how these T lymphocyte populations contribute to disease is essential to develop targeted therapeutics. To this end, several key antigenic T lymphocyte epitopes have been identified and studied to understand their contributions to disease with the aim of developing effective treatment approaches for translation to the clinical setting. In this review, we discuss the role of pathogenic islet-specific T lymphocyte responses in autoimmune diabetes, the mechanisms and cell types governing autoantigen presentation, and therapeutic strategies targeting such T lymphocyte responses for the amelioration of disease.
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Autoantígenos , Diabetes Mellitus Tipo 1 , Linfocitos T , Humanos , Diabetes Mellitus Tipo 1/inmunología , Autoantígenos/inmunología , Animales , Linfocitos T/inmunología , Epítopos de Linfocito T/inmunología , Células Secretoras de Insulina/inmunología , Autoinmunidad , Activación de Linfocitos/inmunología , Presentación de Antígeno/inmunologíaRESUMEN
CD8 T cells are the predominant effector cells of adaptive immunity in preventing cytomegalovirus (CMV) multiple-organ disease caused by cytopathogenic tissue infection. The mechanism by which CMV-specific, naïve CD8 T cells become primed and clonally expand is of fundamental importance for our understanding of CMV immune control. For CD8 T-cell priming, two pathways have been identified: direct antigen presentation by infected professional antigen-presenting cells (pAPCs) and antigen cross-presentation by uninfected pAPCs that take up antigenic material derived from infected tissue cells. Studies in mouse models using murine CMV (mCMV) and precluding either pathway genetically or experimentally have shown that, in principle, both pathways can congruently generate the mouse MHC/H-2 class-I-determined epitope-specificity repertoire of the CD8 T-cell response. Recent studies, however, have shown that direct antigen presentation is the canonical pathway when both are accessible. This raised the question of why antigen cross-presentation is ineffective even under conditions of high virus replication thought to provide high amounts of antigenic material for feeding cross-presenting pAPCs. As delivery of antigenic material for cross-presentation is associated with programmed cell death, and as CMVs encode inhibitors of different cell death pathways, we pursued the idea that these inhibitors restrict antigen delivery and thus CD8 T-cell priming by cross-presentation. To test this hypothesis, we compared the CD8 T-cell responses to recombinant mCMVs lacking expression of the apoptosis-inhibiting protein M36 or the necroptosis-inhibiting protein M45 with responses to wild-type mCMV and revertant viruses expressing the respective cell death inhibitors. The data reveal that increased programmed cell death improves CD8 T-cell priming in mice capable of antigen cross-presentation but not in a mutant mouse strain unable to cross-present. These findings strongly support the conclusion that CMV cell death inhibitors restrict the priming of CD8 T cells by antigen cross-presentation.
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Presentación de Antígeno , Linfocitos T CD8-positivos , Reactividad Cruzada , Infecciones por Citomegalovirus , Animales , Linfocitos T CD8-positivos/inmunología , Ratones , Reactividad Cruzada/inmunología , Presentación de Antígeno/inmunología , Infecciones por Citomegalovirus/inmunología , Muromegalovirus/inmunología , Apoptosis , Citomegalovirus/inmunología , Células Presentadoras de Antígenos/inmunología , Ratones Endogámicos C57BL , Antígenos Virales/inmunologíaRESUMEN
Autophagy is a regulated intracellular catabolic process by which invading pathogens, damaged organelles, aggregated proteins, and other macromolecules are degraded in lysosomes. It has been widely appreciated that autophagic activity plays an important role in regulating the development, fate determination, and function of cells in the immune system, including B lymphocytes. Autophagy encompasses several distinct pathways that have been linked to B cell homeostasis and function. While B cell presentation of major histocompatibility complex (MHC) class II-restricted cytosolic antigens to T cells involves both macroautophagy and chaperone-mediated autophagy (CMA), plasma cells and memory B cells mainly rely on macroautophagy for their survival. Emerging evidence indicates that core autophagy factors also participate in processes related to yet clearly distinct from classical autophagy. These autophagy-related pathways, referred to as noncanonical autophagy or conjugation of ATG8 to single membranes (CASM), contribute to B cell homeostasis and functions, including MHC class II-restricted antigen presentation to T cells, germinal center formation, plasma cell differentiation, and recall responses. Dysregulation of B cell autophagy has been identified in several autoimmune and autoinflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease. In this review, we discuss recent advances in understanding the role of canonical and noncanonical autophagy in B cells, including B cell development and maturation, antigen processing and presentation, pathogen-specific antibody responses, cytokine secretion, and autoimmunity. Unraveling the molecular mechanisms of canonical and noncanonical autophagy in B cells will improve our understanding of B cell biology, with implications for the development of autophagy-based immunotherapies.
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Autofagia , Linfocitos B , Humanos , Autofagia/inmunología , Animales , Linfocitos B/inmunología , Linfocitos B/metabolismo , Presentación de Antígeno/inmunología , Homeostasis/inmunología , Transducción de SeñalRESUMEN
Extracellular vesicles (EVs), such as ectosomes and exosomes, contain DNA, RNA, proteins and are encased in a phospholipid bilayer. EVs provide intralumenal cargo for delivery into the cytoplasm of recipient cells with an impact on the function of immune cells, in part because their biogenesis can also intersect with antigen processing and presentation. Motile EVs from activated immune cells may increase the frequency of immune synapses on recipient cells in a proximity-independent manner for local and long-distance modulation of systemic immunity in inflammation, autoimmunity, organ fibrosis, cancer, and infections. Natural and engineered EVs exhibit the ability to impact innate and adaptive immunity and are entering clinical trials. EVs are likely a component of an optimally functioning immune system, with the potential to serve as immunotherapeutics. Considering the evolving evidence, it is possible that EVs could be the original primordial organic units that preceded the creation of the first cell.
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Vesículas Extracelulares , Humanos , Vesículas Extracelulares/inmunología , Vesículas Extracelulares/metabolismo , Animales , Inmunidad Innata/inmunología , Inmunidad Adaptativa/inmunología , Presentación de Antígeno/inmunología , InmunidadRESUMEN
The functions of the natural dsRNA sensors TLR3 (TRIF) and RIG-I (MAVS) are crucial during viral challenge and have not been accurately clarified in adaptive immune responses to rotavirus (RV) infection. In this study, we found that RV infection caused severe pathological damage to the small intestine of TLR3-/- and TRIF-/- mice. Our data found that dendritic cells from TLR3-/- and TRIF-/- mice had impaired Ag presentation to the RV and attenuated initiation of T cells upon viral infection. These attenuated functions resulted in impaired CD4+ T and CD8+ T function in mice lacking TLR3-TRIF signaling postinfection. Additionally, attenuated proliferative capacity of T cells from TLR3-/- and TRIF-/- mice was observed. Subsequently, we observed a significant reduction in the absolute number of memory T cells in the spleen and mesenteric lymph node (MLN) of TRIF-/- recipient mice following RV infection in a bone marrow chimeric model. Furthermore, there was reduced migration of type 2 classical dendritic cells from the intestine to MLNs after RV infection in TLR3-/- and TRIF-/- mice. Notably, RV infection resulted in attenuated killing of spleen and MLN tissues in TRIF-/- and MAVS-/- mice. Finally, we demonstrated that RV infection promoted apoptosis of CD8+ T cells in TRIF-/- and TLR3-/-MAVS-/- mice. Taken together, our findings highlight an important mechanism of TLR3 signaling through TRIF in mucosal T cell responses to RV and lay the foundation for the development of a novel vaccine.
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Proteínas Adaptadoras Transductoras de Señales , Proteínas Adaptadoras del Transporte Vesicular , Células Dendríticas , Ratones Noqueados , Infecciones por Rotavirus , Rotavirus , Transducción de Señal , Receptor Toll-Like 3 , Animales , Receptor Toll-Like 3/inmunología , Ratones , Infecciones por Rotavirus/inmunología , Transducción de Señal/inmunología , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/inmunología , Rotavirus/inmunología , Células Dendríticas/inmunología , Ratones Endogámicos C57BL , Mucosa Intestinal/inmunología , Linfocitos T CD8-positivos/inmunología , Inmunidad Mucosa , Presentación de Antígeno/inmunologíaRESUMEN
Engineering nanovaccines capable of targeting dendritic cells (DCs) is desperately required to maximize antigen cross-presentation to effector immune cells, elicit strong immune responses, and avoid adverse reactions. Here, we showed that glucose transporter 1 (Glut-1) on DCs is a reliable target for delivering antigens to DCs, and thus, a versatile antigen delivery strategy using glucosylated nanovaccines was developed for DC-targeted antigen delivery and tumor immunotherapy. The developed glucosylated ovalbumin-loaded nanovaccines highly accumulated in lymph nodes and efficiently engaged with Glut-1 on DCs to accelerate intracellular antigen delivery and promote DC maturation and antigen presentation, which elicited potent antitumor immunity to prevent and inhibit ovalbumin-expressing melanoma. Moreover, immunotherapeutic experiments in DC- and macrophage-depleted animal models confirmed that the glucosylated nanovaccines functioned mainly through DCs. In addition, the neoantigen-delivering glucosylated nanovaccines were further engineered to elicit tumor-specific immune responses against MC38 tumors. This study offers a DC-targeted antigen delivery strategy for cancer immunotherapy.
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Vacunas contra el Cáncer , Células Dendríticas , Inmunoterapia , Ratones Endogámicos C57BL , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Animales , Vacunas contra el Cáncer/inmunología , Vacunas contra el Cáncer/química , Vacunas contra el Cáncer/administración & dosificación , Ratones , Ovalbúmina/inmunología , Ovalbúmina/química , Nanopartículas/química , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/química , Femenino , Presentación de Antígeno/inmunología , Línea Celular Tumoral , Humanos , NanovacunasRESUMEN
Immune checkpoint blockade (ICB) therapy has achieved broad applicability and durable clinical responses across cancer types. However, the overall response rate remains suboptimal because some patients do not respond or develop drug resistance. The low infiltration of CD8+ cytotoxic T cells (CTLs) in the tumor microenvironment due to insufficient antigen presentation is closely related to the innate resistance to ICB. The duration and spatial distribution of major histocompatibility complex class I (MHC-I) expression on the cell surface is critical for the efficient presentation of endogenous tumor antigens and subsequent recognition and clearance by CTLs. Tumor cells reduce the surface expression of MHC-I via multiple mechanisms to impair antigen presentation pathways and evade immunity and/or develop resistance to ICB therapy. As an increasing number of studies have focused on membrane MHC-I trafficking and degradation in tumor cells, which may impact the effectiveness of tumor immunotherapy. It is necessary to summarize the mechanism regulating membrane MHC-I translocation into the cytoplasm and degradation via the lysosome. We reviewed recent advances in the understanding of endosomal-lysosomal MHC-I transport and highlighted the means exploited by tumor cells to evade detection and clearance by CTLs. We also summarized new therapeutic strategies targeting these pathways to enhance classical ICB treatment and provide new avenues for optimizing cancer immunotherapy.
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Endosomas , Antígenos de Histocompatibilidad Clase I , Inmunoterapia , Lisosomas , Neoplasias , Humanos , Neoplasias/inmunología , Neoplasias/terapia , Neoplasias/tratamiento farmacológico , Neoplasias/metabolismo , Neoplasias/patología , Lisosomas/metabolismo , Endosomas/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Antígenos de Histocompatibilidad Clase I/metabolismo , Inmunoterapia/métodos , Animales , Transporte de Proteínas , Microambiente Tumoral/inmunología , Presentación de Antígeno/inmunología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Inhibidores de Puntos de Control Inmunológico/farmacologíaRESUMEN
The membrane proximal external region (MPER) of the HIV envelope glycoproteins has generated renewed interest after a recent phase I vaccine trial that presented MPER lipid-peptide epitopes demonstrated promise to elicit a broad neutralization response. The antigenicity of MPER is intimately associated with the membrane, and its presentation relies significantly on the lipid composition. This review brings together recent findings on the influence of membranes on the conformation of MPER and its recognition by broadly neutralizing antibodies. Specifically, the review highlights the importance of properly accounting for the balance between protein-protein and membrane-protein interactions in vaccine design.
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Presentación de Antígeno , VIH-1 , VIH-1/inmunología , Humanos , Presentación de Antígeno/inmunología , Membrana Celular/metabolismo , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/químicaRESUMEN
In αß T cells, immunosurveillance is enabled by the αß TCR, which corecognizes peptide, lipid, or small-molecule Ags presented by MHC- and MHC class I-like Ag-presenting molecules, respectively. Although αß TCRs vary in their Ag recognition modes, in general they corecognize the presented Ag and the Ag-presenting molecule and do so in an invariable "end-to-end" manner. Quite distinctly, γδ T cells, by way of their γδ TCR, can recognize ligands that extend beyond the confines of MHC- and MHC class I-like restrictions. From structural studies, it is now becoming apparent that γδ TCR recognition modes can break the corecognition paradigm and deviate markedly from the end-to-end docking mechanisms of αß TCR counterparts. This brief review highlights the emerging portrait of how γδ TCRs can recognize diverse epitopes of their Ags in a manner reminiscent to how Abs recognize Ags.
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Receptores de Antígenos de Linfocitos T gamma-delta , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Humanos , Animales , Presentación de Antígeno/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Epítopos de Linfocito T/inmunología , Linfocitos T/inmunologíaRESUMEN
Foot and mouth disease (FMD) is a highly contagious infection caused by FMD-virus (FMDV) that affects livestock worldwide with significant economic impact. The main strategy for the control is vaccination with FMDV chemically inactivated with binary ethylenimine (FMDVi). In FMDV infection and vaccination, B cell response plays a major role by providing neutralizing/protective antibodies in animal models and natural hosts. Extracellular vesicles (EVs) and small EVs (sEVs) such as exosomes are important in cellular communication. EVs secreted by antigen-presenting cells (APC) like dendritic cells (DCs) participate in the activation of B and T cells through the presentation of native antigen membrane-associated to B cells or by transferring MHC-peptide complexes to T cells and even complete antigens from DCs. In this study, we demonstrate for the first time that APC activated with the FMDVi O1 Campos vaccine-antigens secrete EVs expressing viral proteins/peptides that could stimulate FMDV-specific immune response. The secretion of EVs-FMDVi is a time-dependent process and can only be isolated within the first 24 h post-activation. These vesicles express classical EVs markers (CD9, CD81, and CD63), along with immunoregulatory molecules (MHC-II and CD86). With an average size of 155 nm, they belong to the category of EVs. Studies conducted in vitro have demonstrated that EVs-FMDVi express antigens that can stimulate a specific B cell response against FMDV, including both marginal zone B cells (MZB) and follicular B cells (FoB). These vesicles can also indirectly or directly affect T cells, indicating that they express both B and T epitopes. Additionally, lymphocyte expansion induced by EVs-FMDVi is greater in splenocytes that have previously encountered viral antigens in vivo. The present study sheds light on the role of EVs derived from APC in regulating the adaptive immunity against FMDV. This novel insight contributes to our current understanding of the immune mechanisms triggered by APC during the antiviral immune response. Furthermore, these findings may have practical implications for the development of new vaccine platforms, providing a rational basis for the design of more effective vaccines against FMDV and other viral diseases.
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Células Presentadoras de Antígenos , Antígenos Virales , Linfocitos B , Vesículas Extracelulares , Virus de la Fiebre Aftosa , Fiebre Aftosa , Vacunas Virales , Animales , Virus de la Fiebre Aftosa/inmunología , Vesículas Extracelulares/inmunología , Linfocitos B/inmunología , Fiebre Aftosa/inmunología , Fiebre Aftosa/prevención & control , Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Antígenos Virales/inmunología , Vacunas Virales/inmunología , Proteínas Virales/inmunología , Activación de Linfocitos/inmunología , Células Dendríticas/inmunología , Presentación de Antígeno/inmunologíaRESUMEN
By altering which peptide antigens are presented to CD4+ T cells, adjuvants affect the specificity of the immune response.
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Adyuvantes Inmunológicos , Linfocitos T CD4-Positivos , Adyuvantes Inmunológicos/farmacología , Humanos , Linfocitos T CD4-Positivos/inmunología , Animales , Presentación de Antígeno/inmunologíaRESUMEN
Introduction: The human leukocyte antigen complex (HLA) is essential for inducing specific immune responses to cancer by presenting tumor-associated peptides (TAP) to T cells. Overexpressed tumor associated antigens, mainly cancer-testis antigens (CTA), are outlined as essential targets for immunotherapy in oropharyngeal squamous cell carcinoma (OPSCC). This study assessed the degree to which presentation, gene expression, and antibody response (AR) of TAP, mainly CTA, are correlated in OPSCC patients to evaluate their potential as immunotherapy targets. Materials and methods: Snap-frozen tumor (NLigand/RNA=40), healthy mucosa (NRNA=6), and healthy tonsils (NLigand=5) samples were obtained. RNA-Seq was performed using Illumina HiSeq 2500/NovaSeq 6000 and whole exome sequencing (WES) utilizing NextSeq500. HLA ligands were isolated from tumor tissue using immunoaffinity purification, UHPLC, and analyzed by tandem MS. Antibodies were measured in serum (NAb=27) utilizing the KREX™ CT262 protein array. Data analysis focused on 312 proteins (KREX™ CT262 panel + overexpressed self-proteins). Results: 183 and 94 of HLA class I and II TAP were identified by comparative profiling with healthy tonsils. Genes from 26 TAP were overexpressed in tumors compared to healthy mucosa (LFC>1; FDR<0.05). Low concordance (r=0.25; p<0.0001) was found between upregulated mRNA and class I TAP. The specific mode of correlation of TAP was found to be dependent on clinical parameters. A lack of correlation was observed both between mRNA and class II TAP, as well as between class II tumor-unique TAP (TAP-U) presentation and antibody response (AR) levels. Discussion: This study demonstrates that focusing exclusively on gene transcript levels fails to capture the full extent of TAP presentation in OPSCC. Furthermore, our findings reveal that although CTA are presented at relatively low levels, a few CTA TAP-U show potential as targets for immunotherapy.
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Antígenos de Neoplasias , Neoplasias Orofaríngeas , Humanos , Neoplasias Orofaríngeas/inmunología , Neoplasias Orofaríngeas/genética , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/genética , Masculino , Femenino , Persona de Mediana Edad , Presentación de Antígeno/inmunología , Anciano , Regulación Neoplásica de la Expresión Génica , Formación de Anticuerpos/genética , Formación de Anticuerpos/inmunología , Adulto , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Secuenciación del Exoma , MultiómicaRESUMEN
Ligation of the B cell antigen receptor (BCR) initiates humoral immunity. However, BCR signaling without appropriate co-stimulation commits B cells to death rather than to differentiation into immune effector cells. How BCR activation depletes potentially autoreactive B cells while simultaneously primes for receiving rescue and differentiation signals from cognate T lymphocytes remains unknown. Here, we use a mass spectrometry-based proteomic approach to identify cytosolic/nuclear shuttling elements and uncover transcription factor EB (TFEB) as a central BCR-controlled rheostat that drives activation-induced apoptosis, and concurrently promotes the reception of co-stimulatory rescue signals by supporting B cell migration and antigen presentation. CD40 co-stimulation prevents TFEB-driven cell death, while enhancing and prolonging TFEB's nuclear residency, which hallmarks antigenic experience also of memory B cells. In mice, TFEB shapes the transcriptional landscape of germinal center B cells. Within the germinal center, TFEB facilitates the dark zone entry of light-zone-residing centrocytes through regulation of chemokine receptors and, by balancing the expression of Bcl-2/BH3-only family members, integrates antigen-induced apoptosis with T cell-provided CD40 survival signals. Thus, TFEB reprograms antigen-primed germinal center B cells for cell fate decisions.
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Apoptosis , Linfocitos B , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice , Antígenos CD40 , Centro Germinal , Receptores de Antígenos de Linfocitos B , Animales , Centro Germinal/inmunología , Centro Germinal/citología , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Linfocitos B/inmunología , Linfocitos B/metabolismo , Ratones , Antígenos CD40/metabolismo , Antígenos CD40/inmunología , Receptores de Antígenos de Linfocitos B/metabolismo , Receptores de Antígenos de Linfocitos B/inmunología , Ratones Endogámicos C57BL , Activación de Linfocitos/inmunología , Diferenciación Celular/inmunología , Transducción de Señal , Presentación de Antígeno/inmunologíaRESUMEN
Numerous developments have been achieved in the study and treatment of cancer throughout the decades that it has been common. After decades of research, about 100 different kinds of cancer have been found, each with unique subgroups within certain organs. This has significantly expanded our understanding of the illness. A mix of genetic, environmental, and behavioral variables contribute to the complicated and diverse process of cancer formation. Mutations, or changes in the DNA sequence, are crucial to the development of cancer. These mutations have the ability to downregulate the expression and function of Major Histocompatibility Complex class I (MHC I) and MHCII receptors, as well as activate oncogenes and inactivate tumor suppressor genes. Cancer cells use this tactic to avoid being recognized by cytotoxic CD8+T lymphocytes, which causes issues with antigen presentation and processing. This review goes into great length into the PI3K pathway, changes to MHC I, and positive impacts of tsMHC-II on disease-free survival and overall survival and the involvement of dendritic cells (DCs) in different tumor microenvironments. The vital functions that the PI3K pathway and its link to the mTOR pathway are highlighted and difficulties in developing effective cancer targeted therapies and feedback systems has also been mentioned, where resistance mechanisms include RAS-mediated oncogenic changes and active PI3K signalling.
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Presentación de Antígeno , Carcinogénesis , Neoplasias , Transducción de Señal , Humanos , Neoplasias/inmunología , Neoplasias/patología , Presentación de Antígeno/inmunología , Carcinogénesis/inmunología , Carcinogénesis/genética , Microambiente Tumoral/inmunología , Antígenos de Neoplasias/inmunología , Antígenos de Neoplasias/metabolismo , Animales , Fosfatidilinositol 3-Quinasas/metabolismoRESUMEN
The thymus is the organ where functional and self-tolerant T cells are selected through processes of positive and negative selection before migrating to the periphery. The antigenic peptides presented on MHC class I molecules of thymic epithelial cells (TECs) in the cortex and medulla of the thymus are key players in these processes. It has been theorized that these cells express different proteasome isoforms, which generate MHC class I immunopeptidomes with features that differentiate cortex and medulla, and hence positive and negative CD8+ T cell selection. This theory is largely based on mouse models and does not consider the large variety of noncanonical antigenic peptides that could be produced by proteasomes and presented on MHC class I molecules. Here, we review the multi-omics, biochemical and cellular studies carried out on mouse models and human thymi to investigate their content of proteasome isoforms, briefly summarize the implication that noncanonical antigenic peptide presentation in the thymus could have on CD8+ T cell repertoire and put these aspects in the larger framework of anatomical and immunological differences between these two species.
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Complejo de la Endopetidasa Proteasomal , Isoformas de Proteínas , Timo , Animales , Humanos , Complejo de la Endopetidasa Proteasomal/metabolismo , Ratones , Timo/inmunología , Timo/metabolismo , Isoformas de Proteínas/metabolismo , Presentación de Antígeno/inmunología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Antígenos de Histocompatibilidad Clase I/metabolismo , Antígenos de Histocompatibilidad Clase I/inmunología , Modelos AnimalesRESUMEN
Upregulation of diverse self-antigens that constitute components of the inflammatory response overlaps spatially and temporally with the emergence of pathogen-derived foreign antigens. Therefore, discrimination between these inflammation-associated self-antigens and pathogen-derived molecules represents a unique challenge for the adaptive immune system. Here, we demonstrate that CD8+ T cell tolerance to T cell-derived inflammation-associated self-antigens is efficiently induced in the thymus and supported by redundancy in cell types expressing these molecules. In addition to thymic epithelial cells, this included thymic eosinophils and innate-like T cells, a population that expressed molecules characteristic for all major activated T cell subsets. We show that direct T cell-to-T cell antigen presentation by minute numbers of innate-like T cells was sufficient to eliminate autoreactive CD8+ thymocytes. Tolerance to such effector molecules was of critical importance, as its breach caused by decreased thymic abundance of a single model inflammation-associated self-antigen resulted in autoimmune elimination of an entire class of effector T cells.