RESUMEN
Amphioxus (e.g., Branchiostoma belcheri, Bb) has recently emerged as a new model for studying the origin and evolution of vertebrate immunity. Mammalian lymphocyte-specific tyrosine kinase (Lck) plays crucial roles in T cell activation, differentiation and homeostasis, and is reported to phosphorylate both the ITIM and ITSM of PD-1 to induce the recruitment of phosphatases and thus the inhibitory function of PD-1. Here, we identified and cloned the amphioxus homolog of human Lck. By generating and using an antibody against BbLck, we found that BbLck is expressed in the amphioxus gut and gill. Through overexpression of BbLck in Jurkat T cells, we found that upon TCR stimulation, BbLck was subjected to tyrosine phosphorylation and could partially rescue Lck-dependent tyrosine phosphorylation in Lck-knockdown T cells. Mass spectrometric analysis of BbLck immunoprecipitates from immunostimulants-treated amphioxus, revealed a BbLck-associated membrane-bound receptor LRR (BbLcLRR). By overexpressing BbLcLRR in Jurkat T cells, we demonstrated that BbLcLRR was tyrosine phosphorylated upon TCR stimulation, which was inhibited by Lck knockdown and was rescued by overexpression of BbLck. By mutating single tyrosine to phenylalanine (Y-F), we identified three tyrosine residues (Y539, Y655, and Y690) (3Y) of BbLcLRR as the major Lck phosphorylation sites. Reporter gene assays showed that overexpression of BbLcLRR but not the BbLcLRR-3YF mutant inhibited TCR-induced NF-κB activation. In Lck-knockdown T cells, the decline of TCR-induced IL-2 production was reversed by overexpression of BbLck, and this reversion was inhibited by co-expression of BbLcLRR but not the BbLcLRR-3YF mutant. Sequence analysis showed that the three tyrosine-containing sequences were conserved with the tyrosine-based inhibition motifs (ITIMs) or ITIM-like motifs. And TCR stimulation induced the association of BbLcLRR with tyrosine phosphatases SHIP1 and to a lesser extent with SHP1/2. Moreover, overexpression of wild-type BbLcLRR but not its 3YF mutant inhibited TCR-induced tyrosine phosphorylation of multiple signaling proteins probably via recruiting SHIP1. Thus, we identified a novel immunoreceptor BbLcLRR, which is phosphorylated by Lck and then exerts a phosphorylation-dependent inhibitory role in TCR-mediated T-cell activation, implying a mechanism for the maintenance of self-tolerance and homeostasis of amphioxus immune system and the evolutionary conservatism of Lck-regulated inhibitory receptor pathway.
Asunto(s)
Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Anfioxos/metabolismo , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/metabolismo , Animales , Biomarcadores , Clonación Molecular , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Bases de Datos Genéticas , Ensayo de Inmunoadsorción Enzimática , Perfilación de la Expresión Génica , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Inmunofenotipificación , Interleucina-2/biosíntesis , Células Jurkat , Anfioxos/genética , Activación de Linfocitos , Proteína Tirosina Quinasa p56(lck) Específica de Linfocito/genética , Fosforilación , Conejos , Receptores de Antígenos de Linfocitos T/metabolismo , Análisis de Secuencia de ADN , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
Inborn errors of immunity are diseases of the immune system resulting from mutations that alter the expression of encoded proteins or molecules. Total updated number of these disorders is currently 406, with 430 different identified gene defects involved. Studies of the underlying mechanisms have contributed in better understanding the pathophysiology of the diseases, but also the complexity of the biology of innate and adaptive immune system and its interaction with microbes. In this review we present and briefly discuss Inborn Errors of Immunity caused by defects in genes encoding for receptors and protein of cellular membrane, including cytokine receptors, T cell antigen receptor (TCR) complex, cellular surface receptors or receptors signaling causing predominantly antibody deficiencies, co-stimulatory receptors and others. These alterations impact many biological processes of immune-system cells, including development, proliferation, activation and down-regulation of the immunological response, and result in a variety of diseases that present with distinct clinical features or with overlapping signs and symptoms.
Asunto(s)
Enfermedades del Sistema Inmune/genética , Proteínas de la Membrana/genética , Mutación , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Humanos , Enfermedades del Sistema Inmune/inmunología , Inmunidad Celular/genética , Síndromes de Inmunodeficiencia/genética , Síndromes de Inmunodeficiencia/inmunología , Enfermedades de Inmunodeficiencia Primaria/genética , Enfermedades de Inmunodeficiencia Primaria/inmunología , Receptores de Antígenos de Linfocitos T/genética , Receptores de Superficie Celular/genética , Receptores de Citocinas/genéticaRESUMEN
The hallmarks of the adaptive immune response are specificity and memory. The cellular response is mediated by T cells which express cell surface T cell receptors (TCRs) that recognize peptide antigens in complex with major histocompatibility complex (MHC) molecules on antigen presenting cells (APCs). However, binding of cognate TCRs with MHC-peptide complexes alone (signal 1) does not trigger optimal T cell activation. In addition to signal 1, the binding of positive and negative costimulatory receptors to their ligands modulates T cell activation. This complex signaling network prevents aberrant activation of T cells. CD28 is the main positive costimulatory receptor on nai¨ve T cells; upon activation, CTLA4 is induced but reduces T cell activation. Further studies led to the identification of additional negative costimulatory receptors known as checkpoints, e.g. PD1. This review chronicles the basic studies in T cell costimulation that led to the discovery of checkpoint inhibitors, i.e. antibodies to negative costimulatory receptors (e.g. CTLA4 and PD1) which reduce tumor growth. This discovery has been recognized with the award of the 2018 Nobel prize in Physiology/Medicine. This review highlights the structural and functional roles of costimulatory receptors, the mechanisms by which checkpoint inhibitors work, the challenges encountered and future prospects.
Asunto(s)
Receptores Coestimuladores e Inhibidores de Linfocitos T/fisiología , Inhibidores de Puntos de Control Inmunológico/farmacología , Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Neoplasias/tratamiento farmacológico , Linfocitos T/inmunología , Células Presentadoras de Antígenos/inmunología , Antígenos CD28/química , Antígenos CD28/metabolismo , Antígeno CTLA-4/química , Antígeno CTLA-4/metabolismo , Receptores Coestimuladores e Inhibidores de Linfocitos T/química , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Humanos , Activación de Linfocitos , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T/fisiologíaRESUMEN
Inhibitory receptors (IR) are a diverse group of cell surface molecules that modulate T cell activation, but there are gaps in our knowledge of the cell-extrinsic factors that regulate their expression. The present study found that in vivo overexpression of IL-27 in mice led to increased T cell expression of PD-L1, LAG-3, TIGIT, and TIM-3. In vitro, TCR stimulation alone promoted expression of multiple IRs, whereas IL-27 alone induced expression of PD-L1. However, the combination of intermediate TCR stimulation and IL-27 resulted in synergistic induction of LAG-3, CTLA-4, and TIGIT. In vivo, infection with Toxoplasma gondii resulted in parasite-specific effector T cells that expressed high levels of IR, and at local sites of infection where IL-27 production was highest, IL-27 was required for maximal effector cell expression of PD-L1, LAG-3, CTLA-4, and TIGIT. Together, these results affirm the critical role of TCR signals in the induction of IR expression but find that during infection, IL-27 promotes T cell expression of IR.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Interleucinas/metabolismo , Receptores de Antígenos de Linfocitos T/metabolismo , Animales , Antígeno B7-H1/metabolismo , Linfocitos T CD4-Positivos/parasitología , Linfocitos T CD8-positivos/parasitología , Antígeno CTLA-4/metabolismo , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Femenino , Interleucinas/genética , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Receptores de Antígenos de Linfocitos T/genética , Receptores Inmunológicos/metabolismo , Bazo/patología , Toxoplasma , Toxoplasmosis/inmunología , Transcriptoma , TransfecciónRESUMEN
Carcinoma-associated pancreatic fibroblasts (CAFs) are the major type of cells in the stroma of pancreatic ductal adenocarcinomas and besides their pathological release of extracellular matrix proteins, they are also perceived as key contributors to immune evasion. Despite the known relevance of tumor infiltrating lymphocytes in cancers, the interactions between T-cells and CAFs remain largely unexplored. Here, we found that CAFs isolated from tumors of pancreatic cancer patients undergoing surgical resection (n = 15) expressed higher levels of the PD-1 ligands PD-L1 and PD-L2 compared to primary skin fibroblasts from healthy donors. CAFs strongly inhibited T-cell proliferation in a contact-independent fashion. Blocking the activity of prostaglandin E2 (PGE2) by indomethacin partially restored the proliferative capacity of both CD4+ and CD8+ T-cells. After stimulation, the proportion of proliferating T-cells expressing HLA-DR and the proportion of memory T-cells were decreased when CAFs were present compared to T-cells proliferating in the absence of CAFs. Interestingly, CAFs promoted the expression of TIM-3, PD-1, CTLA-4 and LAG-3 in proliferating T-cells. Immunohistochemistry stainings further showed that T-cells residing within the desmoplastic stromal compartment express PD-1, indicating a role for CAFs on co-inhibitory marker expression also in vivo. We further found that PGE2 promoted the expression of PD-1 and TIM-3 on T-cells. Functional assays showed that proliferating T-cells expressing immune checkpoints produced less IFN-γ, TNF-α, and CD107a after restimulation when CAFs had been present. Thus, this indicates that CAFs induce expression of immune checkpoints on CD4+ and CD8+ T-cells, which contribute to a diminished immune function.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Fibroblastos Asociados al Cáncer/metabolismo , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Neoplasias Pancreáticas/etiología , Neoplasias Pancreáticas/metabolismo , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Femenino , Regulación Neoplásica de la Expresión Génica , Humanos , Inmunohistoquímica , Inmunomodulación , Inmunofenotipificación , Activación de Linfocitos/genética , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias Pancreáticas/patología , Neoplasias Pancreáticas/terapia , Carga Tumoral , Neoplasias PancreáticasRESUMEN
Exhausted T cells have been described in cancer patients and murine tumor models largely based on their expression of various inhibitory receptors. Understanding of the functional attributes of these cells is limited. Here, we report that among CD8+ T cells in commonly used syngeneic tumor models, the coexpression of inhibitory receptors PD-1, LAG3, and TIM3 defined a group of highly activated and functional effector cells. Coexpression of these receptors further enriched for antigen-specific cells with increased T-cell receptor clonality. Anti-PD-L1 treatment increased the number and activation of these triple-positive CD8+ T cells without affecting the density of PD-1- cells. The intratumoral density of CD8+ T cells coexpressing inhibitory receptors negatively correlated with tumor burden. The density ratio and pretreatment phenotype of CD8+ T cells coexpressing inhibitory receptors was positively correlated with response across a variety of tumor models. Our results demonstrate that coexpression of inhibitory receptors is not a signifier of exhausted T cells, but rather can define a group of activated and functional effector cells in syngeneic tumor models. In the cancer setting, these cells could represent a heterogeneous population of not only exhausted but also highly activated cells responsive to treatment.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Neoplasias/etiología , Neoplasias/metabolismo , Animales , Antígeno B7-H1/antagonistas & inhibidores , Biomarcadores de Tumor , Línea Celular Tumoral , Citotoxicidad Inmunológica , Modelos Animales de Enfermedad , Epítopos de Linfocito T/inmunología , Femenino , Factor Nuclear 1-alfa del Hepatocito/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Isoinjertos , Ratones , Neoplasias/patología , Proteínas de Dominio T Box/genética , Proteínas de Dominio T Box/metabolismoRESUMEN
Gemcitabine plus cisplatin remains the standard first-line systemic therapy for advanced cholangiocarcinoma and offers a median survival of approximately 1 year. No standard regimens beyond the first line and no targeted or immunotherapy agents are approved yet in this disease. Development of molecular targeted therapy in this heterogenous and relatively rare malignancy continues to be a challenging area. The rapidly growing precision medicine efforts have uncovered the underlying mutational landscape of this lethal disease and paved the way for molecularly oriented clinical trials. The early results from such trials like those exploring IDH and FGFR2 derangements have highlighted its promising potential as alternative therapeutic options. Additionally, advances in cancer immunology have identified certain correlates as biomarkers of response to immune modulatory approaches. For instance, the presence of tumor DNA mismatch repair (MMR) deficiency and/or microsatellite instability (MSI), in 5% to 10% of cholangiocarcinoma, is associated with high rates and durability of responses to immune checkpoint blockade. Beside checkpoint inhibitors, other types of immune therapeutics like peptide and dendritic cell-based vaccines and adoptive cell therapies have been developed and are undergoing active evaluation in cholangiocarcinoma. With further research effort, the integration of tumor molecular profiling in trials exploring targeted immunotherapy will lead to better understanding of the predictive role of various molecular and immune biomarkers and ultimately shine the horizon for this patient population.
Asunto(s)
Neoplasias de los Conductos Biliares/tratamiento farmacológico , Biomarcadores de Tumor/antagonistas & inhibidores , Colangiocarcinoma/tratamiento farmacológico , Inmunoterapia/métodos , Antineoplásicos Inmunológicos/farmacología , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de los Conductos Biliares/genética , Neoplasias de los Conductos Biliares/inmunología , Neoplasias de los Conductos Biliares/patología , Productos Biológicos/farmacología , Productos Biológicos/uso terapéutico , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Vacunas contra el Cáncer/uso terapéutico , Colangiocarcinoma/genética , Colangiocarcinoma/inmunología , Colangiocarcinoma/patología , Terapia Combinada/métodos , Terapia Combinada/tendencias , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Reparación de la Incompatibilidad de ADN , Humanos , Inmunoterapia/tendencias , Isocitrato Deshidrogenasa/genética , Inestabilidad de Microsatélites , Terapia Molecular Dirigida/métodos , Receptor Tipo 2 de Factor de Crecimiento de Fibroblastos/genética , Resultado del TratamientoRESUMEN
MiRNA targeting of key immunoregulatory molecules fine-tunes the immune response. This mechanism boosts or dampens immune functions to preserve homeostasis while supporting the full development of effector functions. MiRNA expression changes during T cell activation, highlighting that their function is constrained by a specific spatiotemporal frame related to the signals that induce T cell-based effector functions. Here, we update the state of the art regarding the miRNAs that are differentially expressed during T cell stimulation. We also revisit the existing data on miRNA function in T cell activation, with a special focus on the modulation of the most relevant immunoregulatory molecules.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Regulación de la Expresión Génica/inmunología , Activación de Linfocitos/genética , MicroARNs/metabolismo , Animales , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/inmunología , Proteínas de Ciclo Celular/metabolismo , Supervivencia Celular/genética , Supervivencia Celular/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Citocinas/genética , Citocinas/inmunología , Citocinas/metabolismo , Perfilación de la Expresión Génica , Humanos , Ratones , MicroARNs/inmunología , Modelos AnimalesRESUMEN
The NCCN Guidelines Panel for Melanoma debuted new guidelines for uveal melanoma at the NCCN 23rd Annual Conference. Although uveal melanoma and cutaneous melanoma share the same name, they do have different characteristics and treatments. The NCCN Guidelines describe how tumor size guides therapeutic options, which for most tumors is radiotherapy. Predictors of melanoma-related mortality include advanced age, larger tumor size, and histopathologic and molecular features. The NCCN Guidelines for Cutaneous Melanoma have not changed notably, but adjuvant therapy with immunotherapies is now recommended. The best second-line treatment in the metastatic setting remains unclear.
Asunto(s)
Neoplasias Hepáticas/terapia , Melanoma/terapia , Recurrencia Local de Neoplasia/terapia , Neoplasias Cutáneas/terapia , Sociedades Médicas/normas , Neoplasias de la Úvea/terapia , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Biomarcadores de Tumor/antagonistas & inhibidores , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Braquiterapia/métodos , Braquiterapia/normas , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Enucleación del Ojo/métodos , Enucleación del Ojo/normas , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/secundario , Metástasis Linfática/patología , Metástasis Linfática/radioterapia , Oncología Médica/normas , Melanoma/genética , Melanoma/inmunología , Melanoma/patología , Terapia Neoadyuvante/métodos , Terapia Neoadyuvante/normas , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/inmunología , Recurrencia Local de Neoplasia/patología , Estadificación de Neoplasias , Inhibidores de Proteínas Quinasas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas B-raf/antagonistas & inhibidores , Proteínas Proto-Oncogénicas B-raf/genética , Ensayos Clínicos Controlados Aleatorios como Asunto , Neoplasias Cutáneas/genética , Neoplasias Cutáneas/inmunología , Neoplasias Cutáneas/patología , Estados Unidos , Neoplasias de la Úvea/genética , Neoplasias de la Úvea/inmunología , Neoplasias de la Úvea/patologíaRESUMEN
The so-called shock and kill therapies aim to combine HIV-1 reactivation by latency-reversing agents (LRA) with immune clearance to purge the HIV-1 reservoir. The clinical use of LRA has demonstrated detectable perturbations in the HIV-1 reservoir without measurable reductions to date. Consequently, fundamental questions concerning the limitations of the recognition and killing of LRA-reactivated cells by effector cells such as CD8+ T cells remain to be answered. Here, we developed a novel experimental framework where we combine the use of cytotoxic CD8+ T-cell lines and ex vivo CD8+ T cells from HIV-1-infected individuals with functional assays of LRA-inducible reactivation to delineate immune barriers to clear the reservoir. Our results demonstrate the potential for early recognition and killing of reactivated cells by CD8+ T cells. However, the potency of LRAs when crossing the barrier for antigen presentation in target cells, together with the lack of expression of inhibitory receptors in CD8+ T cells, are critical events to maximize the speed of recognition and the magnitude of the killing of LRA-inducible provirus. Taken together, our findings highlight direct limitations in LRA potency and CD8+ T cell functional status to succeed in the cure of HIV-1 infection.
Asunto(s)
Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Infecciones por VIH/inmunología , VIH-1/fisiología , Activación Viral/inmunología , Latencia del Virus/inmunología , Presentación de Antígeno , Antígenos Virales/inmunología , Biomarcadores , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Citotoxicidad Inmunológica , Infecciones por VIH/metabolismo , Infecciones por VIH/virología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Inmunofenotipificación , Linfocitos T Citotóxicos/inmunología , Linfocitos T Citotóxicos/metabolismo , Carga ViralRESUMEN
Adoptive T-lymphocyte transfer-based immunotherapy for cancers has seen huge leaps with both CARs and engineered TCRs. Despite this, issues relating to safety and efficacy persist. To address this, chimeric switch receptors have been created to reverse the outcomes of their original signaling pathways in order to confer immune cells with the ability to overcome the immunosuppressive tumor microenvironment and to allow them to have greater in vivo persistence. Activating switch receptors exploit the inhibitory molecules expressed by cancer cells to further stimulate the tumor antigen-specific T lymphocytes. On the other hand, inhibitory switch receptors inhibit the effects of tumor-reactive T lymphocytes on unintended targets. This paper reviews the switch receptors reported thus far, and lists out potential improvements and future works.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T/inmunología , Antígenos de Neoplasias/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Ingeniería Genética , Humanos , Neoplasias/inmunología , Proteínas Recombinantes de Fusión/genética , Linfocitos T/trasplante , Microambiente TumoralRESUMEN
Inhibitory receptors have been extensively described for their importance in regulating immune responses in chronic infections and cancers. Blocking the function of inhibitory receptors such as PD-1, CTLA-4, 2B4, Tim-3, and LAG-3 has shown promise for augmenting CD8 T cell activity and boosting pathogen-specific immunity. However, the prevalence of inhibitory receptors on CD4 T cells and their relative influence on CD4 T cell functionality in chronic HIV infection remains poorly described. We therefore determined and compared inhibitory receptor expression patterns of 2B4, CTLA-4, LAG-3, PD-1, and Tim-3 on virus-specific CD4 and CD8 T cells in relation to their functional T cell profile. In chronic HIV infection, inhibitory receptor distribution differed markedly between cytokine-producing T cell subsets with, gamma interferon (IFN-γ)- and tumor necrosis factor alpha (TNF-α)-producing cells displaying the highest and lowest prevalence of inhibitory receptors, respectively. Blockade of inhibitory receptors differentially affected cytokine production by cells in response to staphylococcal enterotoxin B stimulation. CTLA-4 blockade increased IFN-γ and CD40L production, while PD-1 blockade strongly augmented IFN-γ, interleukin-2 (IL-2), and TNF-α production. In a Friend retrovirus infection model, CTLA-4 blockade in particular was able to improve control of viral replication. Together, these results show that inhibitory receptor distribution on HIV-specific CD4 T cells varies markedly with respect to the functional subset of CD4 T cells being analyzed. Furthermore, the differential effects of receptor blockade suggest novel methods of immune response modulation, which could be important in the context of HIV vaccination or therapeutic strategies.IMPORTANCE Inhibitory receptors are important for limiting damage by the immune system during acute infections. In chronic infections, however, their expression limits immune system responsiveness. Studies have shown that blocking inhibitory receptors augments CD8 T cell functionality in HIV infection, but their influence on CD4 T cells remains unclear. We assessed the expression of inhibitory receptors on HIV-specific CD4 T cells and their relationship with T cell functionality. We uncovered differences in inhibitory receptor expression depending on the CD4 T cell function. We also found differences in functionality of CD4 T cells following blocking of different inhibitory receptors, and we confirmed our results in a Friend virus retroviral model of infection in mice. Our results show that inhibitory receptor expression on CD4 T cells is linked to CD4 T cell functionality and could be sculpted by blockade of specific inhibitory receptors. These data reveal exciting possibilities for the development of novel treatments and immunotherapeutics.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Expresión Génica , Infecciones por VIH/inmunología , Animales , Anticuerpos/administración & dosificación , Anticuerpos/farmacología , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/virología , Antígeno CTLA-4/antagonistas & inhibidores , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/efectos de los fármacos , Citocinas/biosíntesis , Citocinas/efectos de los fármacos , Enterotoxinas/farmacología , Virus de la Leucemia Murina de Friend/fisiología , Infecciones por VIH/virología , Humanos , Interferón gamma/biosíntesis , Ratones , Receptor de Muerte Celular Programada 1/antagonistas & inhibidores , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/inmunología , Infecciones por Retroviridae/inmunología , Factor de Necrosis Tumoral alfa/biosíntesisRESUMEN
OBJECTIVE: Immune cells play a critical role in atherosclerosis. Costimulatory and coinhibitory molecules of the tumor necrosis factor receptor and CD28 immunoglobulin superfamilies not only shape T-cell and B-cell responses but also have a major effect on antigen-presenting cells and nonimmune cells. APPROACH AND RESULTS: Pharmacological inhibition or activation of costimulatory and coinhibitory molecules and genetic deletion demonstrated their involvement in atherosclerosis. This review highlights recent advances in understanding how costimulatory and coinhibitory pathways shape the immune response in atherosclerosis. CONCLUSIONS: Insights gained from costimulatory and coinhibitory molecule function in atherosclerosis may inform future therapeutic approaches.
Asunto(s)
Arterias/inmunología , Aterosclerosis/inmunología , Linfocitos B/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Linfocitos T/inmunología , Animales , Anticuerpos/uso terapéutico , Arterias/efectos de los fármacos , Arterias/metabolismo , Arterias/patología , Aterosclerosis/tratamiento farmacológico , Aterosclerosis/genética , Aterosclerosis/metabolismo , Linfocitos B/efectos de los fármacos , Linfocitos B/metabolismo , Antígenos CD28/inmunología , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Humanos , Inmunoterapia/métodos , Terapia Molecular Dirigida , Receptores del Factor de Necrosis Tumoral/inmunología , Transducción de Señal , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismoRESUMEN
Hepatitis C virus (HCV)-specific CD4+ and CD8+ T cells are key to successful viral clearance in HCV disease. Accumulation of exhausted HCV-specific T cells during chronic infection results in considerable loss of protective functional immune responses. The role of T-cell exhaustion in chronic HCV disease remains poorly understood. Here, we studied the frequency of HCV peptide-stimulated T cells expressing negative immune checkpoints (PD-1, CTLA-4, TRAIL, TIM-3 and BTLA) by flow cytometry, and measured the levels of Th1/Th2/Th17 cytokines secreted by T cells by a commercial Multi-Analyte ELISArray™ following in vitro stimulation of T cells using HCV peptides and phytohemagglutinin (PHA). HCV peptide-stimulated CD4+ and CD8+ T cells of chronic HCV (CHC) patients showed significant increase of CTLA-4. Furthermore, HCV peptide-stimulated CD4+ T cells of CHC patients also displayed relatively higher levels of PD-1 and TRAIL, whereas TIM-3 was up-regulated on HCV peptide-stimulated CD8+ T cells. Whereas the levels of IL-10 and TGF-ß1 were significantly increased, the levels of pro-inflammatory cytokines IL-2, TNF-α, IL-17A and IL-6 were markedly decreased in the T cell cultures of CHC patients. Chronic HCV infection results in functional exhaustion of CD4+ and CD8+ T cells likely contributing to viral persistence.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Hepacivirus/inmunología , Hepatitis C Crónica/inmunología , Inmunosenescencia , Adulto , Anciano , Anciano de 80 o más Años , Antígenos Virales/inmunología , Linfocitos T CD8-positivos/virología , Células Cultivadas , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Citocinas/metabolismo , Humanos , Mediadores de Inflamación/metabolismo , Persona de Mediana Edad , Fragmentos de Péptidos/inmunología , Carga Viral , Adulto JovenRESUMEN
Hematopoietic cell transplantation (HCT) remains an important and potentially curative option for most hematologic malignancies. As a form of immunotherapy, allogeneic HCT (allo-HCT) offers the potential for durable remissions but is limited by transplantation- related morbidity and mortality owing to organ toxicity, infection, and graft-versus-host disease. The recent positive outcomes of chimeric antigen receptor T (CART) cell therapy in B cell malignancies may herald a paradigm shift in the management of these disorders and perhaps other hematologic malignancies as well. Clinical trials are now needed to address the relative roles of CART cells and HCT in the context of transplantation-eligible patients. In this review, we summarize the state of the art of the development of CART cell therapy for leukemia, lymphoma, and myeloma and discuss our perspective of how CART cell therapy can be applied in the context of HCT.
Asunto(s)
Enfermedad Injerto contra Huésped/prevención & control , Trasplante de Células Madre Hematopoyéticas , Inmunoterapia Adoptiva , Receptores de Antígenos de Linfocitos T/inmunología , Linfocitos T/trasplante , Antígenos CD/genética , Antígenos CD/inmunología , Complejo CD3/genética , Complejo CD3/inmunología , Células Cultivadas , Ensayos Clínicos como Asunto , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Genes Sintéticos , Vectores Genéticos , Neoplasias Hematológicas/terapia , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/métodos , Estudios Multicéntricos como Asunto , Dominios Proteicos , Receptores de Antígenos de Linfocitos T/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Anticuerpos de Cadena Única/genética , Anticuerpos de Cadena Única/inmunología , Linfocitos T/inmunología , Transducción Genética , Acondicionamiento PretrasplanteRESUMEN
Epigenetic changes in oncogenes and tumor-suppressor genes contribute to carcinogenesis. Understanding the epigenetic and genetic components of tumor immune evasion is crucial. Few cancer genetic mutations have been linked to direct correlations with immune evasion. Studies on the epigenetic modulation of the immune checkpoints have revealed a critical interaction between epigenetic and immune modulation. Epigenetic modifiers can activate many silenced genes. Some of them are immune checkpoints regulators that turn on immune responses and others turn them off resulting in immune evasion. Many forms of epigenetic inheritance mechanisms may play a role in regulation of immune checkpoints including: covalent modifications, noncoding RNA and histone modifications. In this review, we will show how the potential interaction between epigenetic and immune modulation may lead to new approaches for specific epigenome/immunome-targeted therapies for cancer.
Asunto(s)
Receptores Coestimuladores e Inhibidores de Linfocitos T/metabolismo , Epigénesis Genética , Inmunoterapia/métodos , Neoplasias/terapia , Animales , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Metilación de ADN , Humanos , Inmunomodulación , Terapia Molecular Dirigida , Neoplasias/inmunología , Escape del TumorAsunto(s)
Antineoplásicos Inmunológicos/uso terapéutico , Receptores Coestimuladores e Inhibidores de Linfocitos T/antagonistas & inhibidores , Oncología Médica/métodos , Neoplasias/terapia , Medicina de Precisión/métodos , Antineoplásicos Inmunológicos/farmacología , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Resistencia a Antineoplásicos/genética , Humanos , Neoplasias/genética , Neoplasias/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/inmunología , Linfocitos T/metabolismo , Resultado del TratamientoAsunto(s)
Inmunidad Adaptativa , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Inmunidad Innata , Neoplasias/inmunología , Linfocitos T Reguladores/inmunología , Animales , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Regulación de la Expresión Génica/inmunología , Homeostasis/inmunología , Humanos , Tolerancia Inmunológica , Neoplasias/patología , Transducción de Señal , Linfocitos T Reguladores/patologíaRESUMEN
The immune system evolved to distinguish non-self from self to protect the organism. As cancer is derived from our own cells, immune responses to dysregulated cell growth present a unique challenge. This is compounded by mechanisms of immune evasion and immunosuppression that develop in the tumour microenvironment. The modern genetic toolbox enables the adoptive transfer of engineered T cells to create enhanced anticancer immune functions where natural cancer-specific immune responses have failed. Genetically engineered T cells, so-called 'living drugs', represent a new paradigm in anticancer therapy. Recent clinical trials using T cells engineered to express chimeric antigen receptors (CARs) or engineered T cell receptors (TCRs) have produced stunning results in patients with relapsed or refractory haematological malignancies. In this Review we describe some of the most recent and promising advances in engineered T cell therapy with a particular emphasis on what the next generation of T cell therapy is likely to entail.
Asunto(s)
Inmunoterapia Adoptiva/métodos , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/inmunología , Presentación de Antígeno , Antígenos CD19/inmunología , Antígenos de Neoplasias/inmunología , Ensayos Clínicos como Asunto , Receptores Coestimuladores e Inhibidores de Linfocitos T/genética , Receptores Coestimuladores e Inhibidores de Linfocitos T/inmunología , Citocinas/metabolismo , Predicción , Edición Génica , Técnicas de Transferencia de Gen , Ingeniería Genética , Antígenos HLA/inmunología , Neoplasias Hematológicas/inmunología , Neoplasias Hematológicas/terapia , Humanos , Inmunoterapia Adoptiva/efectos adversos , Inmunoterapia Adoptiva/tendencias , Modelos Inmunológicos , Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/genética , Proteínas Recombinantes de Fusión/genética , Proteínas Recombinantes de Fusión/inmunología , Síndrome , Especificidad del Receptor de Antígeno de Linfocitos T , Subgrupos de Linfocitos T/trasplante , Escape del Tumor , Microambiente Tumoral/inmunologíaRESUMEN
Co-stimulatory and co-inhibitory molecules direct the "second signal," which largely determines the outcome of the "first signal" generated by the interaction of T cell receptor (TCR) with cognate MHC-peptide complex. The co-stimulatory and co-inhibitory signals are key mechanistic contributors to the regulation of adaptive immunity, especially the T cell-mediated immune response. Regulatory T cells (Tregs) are a special population of T cells, which unlike other T cells function as "attenuators" to suppress T cell immunity. Dysregulation of either the "second signal" or Tregs leads to an unbalanced immune system, which can result in a range of immune-related disorders, including autoimmune diseases, chronic infections, and tumors. In contrast, precise manipulation of these two systems offers tremendous clinical opportunities to treat these same diseases. Co-stimulatory and co-inhibitory molecules modulate immunity at molecular level, whereas Tregs delicately control the immune response at cellular level. Accumulating evidence has demonstrated that these two regulatory strategies converge and synergize with each other. This review discusses recent progress on the roles of co-stimulatory and co-inhibitory signals in the context of Tregs.