RESUMEN
Elimination of virally infected or tumoral cells is mediated by cytotoxic T cells (CTL). Upon antigen recognition, CTLs assemble a specialized signaling and secretory domain at the interface with their target, the immune synapse (IS). During IS formation, CTLs acquire a transient polarity, marked by re-orientation of the centrosome and microtubule cytoskeleton toward the IS, thus directing the transport and delivery of the lytic granules to the target cell. Based on the implication that the kinase Aurora A has a role in CTL function, we hypothesized that its substrate, the mitotic regulator Polo-like kinase 1 (PLK1), might participate in CTL IS assembly. We demonstrate that PLK1 is phosphorylated upon TCR triggering and polarizes to the IS. PLK1 silencing or inhibition results in impaired IS assembly and function, as witnessed by defective synaptic accumulation of T cell receptors (TCRs), as well as compromised centrosome and lytic granule polarization to the IS, resulting in impaired target cell killing. This function is achieved by coupling early signaling to microtubule dynamics, a function pivotal for CTL-mediated cytotoxicity. These results identify PLK1 as a new player in CTL IS assembly and function.
Asunto(s)
Quinasa Tipo Polo 1 , Linfocitos T Citotóxicos , Linfocitos T Citotóxicos/metabolismo , Centrosoma/metabolismo , Transducción de Señal , Microtúbulos/metabolismo , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismoRESUMEN
It has long been thought that clonal deletion efficiently removes almost all self-specific T cells from the peripheral repertoire. We found that self-peptide MHC-specific CD8(+) T cells in the blood of healthy humans were present in frequencies similar to those specific for non-self antigens. For the Y chromosome-encoded SMCY antigen, self-specific T cells exhibited only a 3-fold lower average frequency in males versus females and were anergic with respect to peptide activation, although this inhibition could be overcome by a stronger stimulus. We conclude that clonal deletion prunes but does not eliminate self-specific T cells and suggest that to do so would create holes in the repertoire that pathogens could readily exploit. In support of this hypothesis, we detected T cells specific for all 20 amino acid variants at the p5 position of a hepatitis C virus epitope in a random group of blood donors.
Asunto(s)
Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Supresión Clonal , Animales , Variación Antigénica , Femenino , Citometría de Flujo , Humanos , Masculino , Ratones , Receptores de Antígenos de Linfocitos T alfa-beta/genética , Autotolerancia/inmunologíaRESUMEN
We have developed a single-molecule imaging technique that uses quantum-dot-labeled peptide-major histocompatibility complex (pMHC) ligands to study CD4(+) T cell functional sensitivity. We found that naive T cells, T cell blasts, and memory T cells could all be triggered by a single pMHC to secrete tumor necrosis factor-α (TNF-α) and interleukin-2 (IL-2) cytokines with a rate of â¼1,000, â¼10,000, and â¼10,000 molecules/min, respectively, and that additional pMHCs did not augment secretion, indicating a digital response pattern. We also found that a single pMHC localized to the immunological synapse induced the slow formation of a long-lasting T cell receptor (TCR) cluster, consistent with a serial engagement mechanism. These data show that scaling up CD4(+) T cell cytokine responses involves increasingly efficient T cell recruitment rather than greater cytokine production per cell.
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Antígenos de Histocompatibilidad Clase II/inmunología , Subgrupos de Linfocitos T/metabolismo , Inmunidad Adaptativa , Secuencia de Aminoácidos , Animales , Presentación de Antígeno , Biotinilación , Linfocitos T CD4-Positivos/efectos de los fármacos , Linfocitos T CD4-Positivos/inmunología , Diferenciación Celular , Inmunoconjugados , Memoria Inmunológica , Sinapsis Inmunológicas , Interleucina-2/metabolismo , Activación de Linfocitos , Datos de Secuencia Molecular , Mariposas Nocturnas , Fragmentos de Péptidos/inmunología , Puntos Cuánticos , Receptores de Antígenos de Linfocitos T alfa-beta/inmunología , Tasa de Secreción , Análisis de la Célula Individual , Subgrupos de Linfocitos T/efectos de los fármacos , Subgrupos de Linfocitos T/inmunología , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
Chimeric antigen receptor (CAR) T cell immunotherapy is a revolutionary pillar in cancer treatment. Clinical experience has shown remarkable successes in the treatment of certain hematological malignancies but only limited efficacy against B cell chronic lymphocytic leukemia (CLL) and other cancer types, especially solid tumors. A wide range of engineering strategies have been employed to overcome the limitations of CAR T cell therapy. However, it has become increasingly clear that CARs have unique, unexpected features; hence, a deep understanding of how CARs signal and trigger the formation of a non-conventional immunological synapse (IS), the signaling platform required for T cell activation and execution of effector functions, would lead a shift from empirical testing to the rational design of new CAR constructs. Here, we review current knowledge of CARs, focusing on their structure, signaling and role in CAR T cell IS assembly. We, moreover, discuss the molecular features accounting for poor responses in CLL patients treated with anti-CD19 CAR T cells and propose CLL as a paradigm for diseases connected to IS dysfunctions that could significantly benefit from the development of novel CARs to generate a productive anti-tumor response.
Asunto(s)
Leucemia Linfocítica Crónica de Células B , Receptores Quiméricos de Antígenos , Humanos , Leucemia Linfocítica Crónica de Células B/terapia , Leucemia Linfocítica Crónica de Células B/metabolismo , Sinapsis Inmunológicas/metabolismo , Linfocitos T , Activación de LinfocitosRESUMEN
There is no therapeutic agent approved in cutaneous mastocytosis and mast cell activation syndrome. We report the efficacy of hydroxychloroquine in four patients with cutaneous mastocytosis (nâ¯=â¯2) and mast cell activation syndrome (nâ¯=â¯2). We show that this molecule reduces the long-term survival of primary human mast cells, interferes with lysosome function and leads to the accumulation of non-functional tryptase in the mast cell granules. Furthermore, hydroxychloroquine decreases the production of pro-inflammatory mediators.
Asunto(s)
Hidroxicloroquina/uso terapéutico , Mastocitosis/tratamiento farmacológico , Humanos , Mediadores de Inflamación/uso terapéutico , Lisosomas/efectos de los fármacos , Masculino , Mastocitos/efectos de los fármacos , Persona de Mediana EdadRESUMEN
BACKGROUND: Mast cells are versatile key components of allergy and inflammation known to respond to both innate and adaptive immunologic stimuli. However, the response of individual mast cells to cumulative stimuli remains poorly understood. OBJECTIVES: We sought to dissect mast cell responses at the single-cell level and their potentiation by IL-33. METHODS: We monitored mast cell degranulation in real time by exploiting the capacity of fluorochrome-labeled avidin to stain degranulating cells. During the degranulation process, the granule matrix is externalized and immediately bound by fluorochrome-labeled avidin present in the culture medium. The degranulation process is monitored by using either time-lapse microscopy or fluorescence-activated cell sorting analysis. RESULTS: Single-cell analysis revealed a strong heterogeneity of individual mast cell degranulation responses. We observed that the number of degranulating mast cells was graded according to the FcεRI stimulation strength, whereas the magnitude of individual mast cell degranulation remained unchanged, suggesting an all-or-none response of mast cells after FcεRI triggering. IL-33 pretreatment increased not only the number of degranulating and chemokine-producing mast cells but also the magnitude of individual mast cell degranulation and chemokine production. CONCLUSION: We illustrate the effect of IL-33 on mast cell biology at the single-cell level by showing that IL-33 potentiates IgE-mediated mast cell responses by both increasing the number of responding cells and enhancing the responses of individual mast cells.
Asunto(s)
Degranulación de la Célula/fisiología , Quimiocinas/metabolismo , Mastocitos/fisiología , Animales , Calcio/metabolismo , Células Cultivadas , Humanos , Inmunoglobulina E/farmacología , Mastocitos/efectos de los fármacos , Ratones , Cavidad Peritoneal/citologíaRESUMEN
The functional role of molecular clustering in the center of the immunological synapse is controversial. In this issue of Immunity, Cemerski et al. (2008) report that the synapse center can serve as a major site of sustained signal transduction.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Uniones Intercelulares/inmunología , Transducción de Señal , Linfocitos T/inmunología , Animales , Células Presentadoras de Antígenos/metabolismo , Comunicación Celular , Humanos , Uniones Intercelulares/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Linfocitos T/metabolismoRESUMEN
It is presently assumed that lethal hit delivery by cytotoxic T lymphocytes (CTLs) is mechanistically linked to centrosome polarization toward target cells, leading to dedicated release of lytic granules within a confined secretory domain. Here we provide three lines of evidence showing that this mechanism might not apply as a general paradigm for lethal hit delivery. First, in CTLs stimulated with immobilized peptide-MHC complexes, lytic granules and microtubule organizing center localization into synaptic areas are spatio-temporally dissociated, as detected by total internal reflection fluorescence microscopy. Second, in many CTL/target cell conjugates, lytic granule secretion precedes microtubule polarization and can be detected during the first minute after cell-cell contact. Third, inhibition of microtubule organizing center and centrosome polarization impairs neither lytic granule release at the CTL synapse nor killing efficiency. Our results broaden current views of CTL biology by revealing an extremely rapid step of lytic granule secretion and by showing that microtubule organizing center polarization is dispensable for efficient lethal hit delivery.
Asunto(s)
Centrosoma/ultraestructura , Sinapsis Inmunológicas , Microtúbulos/metabolismo , Vesículas Secretoras/metabolismo , Linfocitos T Citotóxicos/citología , Polaridad Celular , Centrosoma/metabolismo , Gránulos Citoplasmáticos/metabolismo , Citotoxicidad Inmunológica , Citometría de Flujo , Humanos , Microscopía Confocal , Microscopía Fluorescente , Centro Organizador de los Microtúbulos/ultraestructura , Proteína Quinasa C/metabolismo , Transducción de Señal , Factores de TiempoRESUMEN
BACKGROUND: Mast cells are key components of the skin microenvironment in psoriasis, yet their functional role in this T-cell-mediated inflammatory disorder remains to be elucidated. OBJECTIVE: To define the impact of T-cell/mast-cell cognate interactions on the cytokines produced by TH cells. METHODS: We used human primary mast cells and effector/memory CD4(+) T cells for in vitro coculture experiments, and we analyzed TH cells responses by using cytometry. CD4(+) T-cell/mast-cell conjugates in skin lesions from patients with psoriasis were analyzed by using 3-color immunohistochemistry and confocal microscopy. RESULTS: We show that IFN-γ-primed human mast cells formed productive immunologic synapses with antigen-experienced CD4(+) T cells. These interactions promoted the generation of TH22 and IL-22/IFN-γ-producing TH cells from the circulating memory CD4(+) T-cell pool via a TNF-α/IL-6-dependent mechanism. An analysis of human psoriatic skin biopsies showed a rich infiltrate of IL-22(+)CD4(+) T cells frequently found in contact with mast cells. Moreover, most of these mast-cell-conjugated lymphocytes coexpressed IFN-γ, suggesting that IL-22(+)IFN-γ(+) CD4(+) T cells are generated in vivo on interaction with mast cells. CONCLUSIONS: Our findings identify human mast cells as functional partners of TH cells, shaping their responses toward IL-22 production.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Memoria Inmunológica , Mediadores de Inflamación/fisiología , Interleucinas/biosíntesis , Mastocitos/inmunología , Linfocitos T CD4-Positivos/clasificación , Linfocitos T CD4-Positivos/patología , Comunicación Celular/genética , Comunicación Celular/inmunología , Técnicas de Cocultivo , Humanos , Memoria Inmunológica/genética , Inmunofenotipificación , Mediadores de Inflamación/metabolismo , Interleucinas/genética , Mastocitos/patología , Interleucina-22RESUMEN
Effector CD4+ T lymphocytes (Teff) infiltrate sites of inflammation and orchestrate the immune response by instructing local leukocytes. Mast cells (MCs) are tissue sentinel cells strategically located near blood vessels and T cell rich areas. MC/Teff cells interactions shape Teff cell responses but in turn, Teff cell action on MC is still poorly understood. Here, we analyzed the human MC/Teff cells interplay through both the application of RNAseq and functional assays. We showed that activated Teff cells induce a specific transcriptomic program in MCs including production of both inflammatory cytokines and chemokines, prostaglandin, and a FcεRI-dependent degranulation facilitation thereby driving them toward an inflammatory phenotype. Moreover, Teff cells induce in MCs the capacity to interact with CD4+ T cell through a wide-range of dedicated soluble and membrane ligands and to play the role of antigen presenting cells (APCs).
RESUMEN
CD8+ CTLs are thought to play a role in the control of follicular lymphoma (FL). Yet, the link between CTL tissue distribution, activation status, ability to kill FL cells in vivo, and disease progression is still elusive. Pretreatment lymph nodes from FL patients were analyzed by IHC (n = 80) or by 3-color confocal microscopy (n = 10). IHC revealed a rich infiltrate of CD8+ granzyme B+ (GrzB) cells in FL interfollicular spaces. Accordingly, confocal microscopy showed an increased number of CD3+CD8+GrzB+ CTLs and a brighter GrzB staining in individual CTL in FL samples compared with reactive lymph nodes. CTLs did not penetrate tumor nodules. In 3-dimensional (3-D) image reconstructions, CTLs were detected at the FL follicle border where they formed lytic synapse-like structures with FL B cells and with apoptotic cells, suggesting an in situ cytotoxic function. Finally, although GrzB expression in CTLs did not correlate with risk factors, high GrzB content correlated with prolonged progression free-survival (PFS) after rituximab-combined chemotherapy. Our results show the recruitment of armed CTLs with a tumor-controlling potential into FL lymph nodes and suggest that CTL-associated GrzB expression could influence PFS in FL patients having received rituximab-combined chemotherapy.
Asunto(s)
Imagenología Tridimensional , Ganglios Linfáticos/patología , Linfoma Folicular/epidemiología , Linfoma Folicular/patología , Linfocitos T Citotóxicos/patología , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales de Origen Murino/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Biomarcadores de Tumor/metabolismo , Complejo CD3/metabolismo , Antígenos CD8/metabolismo , Ciclofosfamida/administración & dosificación , Doxorrubicina/administración & dosificación , Femenino , Granzimas/metabolismo , Humanos , Linfoma Folicular/tratamiento farmacológico , Masculino , Microscopía Confocal/métodos , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Prednisona/administración & dosificación , Pronóstico , Factores de Riesgo , Rituximab , Linfocitos T Citotóxicos/metabolismo , Vincristina/administración & dosificaciónRESUMEN
Cognate interactions between T and B lymphocytes lead to the formation of the immunological synapse (IS) where bidirectional activation signals are exchanged. Although the molecular architecture and the function of the IS have been studied extensively on the T cell side, little is known about events occurring during synapse formation in Ag-presenting B cells. We investigated the impact of BCR and TLR signaling on human B cell activation and on the T and B cell side of the IS. On the T cell side, we observed that T cells polarized toward both naive and previously activated B cells. Nevertheless, when T cells interacted with different B cells simultaneously, T cells selectively polarized their secretory machinery toward preactivated B cells. Furthermore, both naive and preactivated B cells reoriented their microtubule-organizing center toward the synaptic T cell during cognate interactions. This phenomenon was rapid and not dependent on T cell secretory activity. Interestingly, not only the microtubule-organizing center but also the Golgi apparatus and Lamp-3(+) and MHC class II(+) vesicles all repositioned beneath the IS, suggesting that the entire endocytic/exocytic B cell compartment was reoriented toward the T cell. Taken together, our results show that the B cell activation status fine-tunes T cell polarization responses and reveal the capacity of naive and activated B cells to polarize toward T cells during cognate interactions.
Asunto(s)
Subgrupos de Linfocitos B/inmunología , Subgrupos de Linfocitos B/metabolismo , Comunicación Celular/inmunología , Polaridad Celular/inmunología , Sinapsis Inmunológicas/metabolismo , Subgrupos de Linfocitos T/inmunología , Animales , Subgrupos de Linfocitos B/citología , Comunicación Celular/genética , Polaridad Celular/genética , Células Cultivadas , Células Clonales , Epítopos de Linfocito B/inmunología , Epítopos de Linfocito T/inmunología , Humanos , Sinapsis Inmunológicas/genética , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Subgrupos de Linfocitos T/citología , Subgrupos de Linfocitos T/metabolismo , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismoRESUMEN
T-cell activation results from productive T-cell receptor (TCR) engagement by a cognate peptide-MHC (pMHC) complex on the antigen presenting cell (APC) surface, a process leading to the polarization of the T-cell secretory machinery toward the APC interface. We have previously shown that the half-life of the TCR/pMHC interaction and the density of pMHC on the APC are two parameters determining T-cell activation. However, whether the half-life of the TCR/pMHC interaction can modulate the efficiency of T-cell secretory machinery polarization toward an APC still remains unclear. Here, by using altered peptide ligands conferring different half-lives to the TCR/pMHC interaction, we have tested how this parameter can control T-cell polarization. We observed that only TCR/pMHC interactions with intermediate half-lives can promote the assembly of synapses that lead to T-cell activation. Strikingly, intermediate half-life interactions can be competed out by short half-life interactions, which can efficiently promote T-cell polarization and antagonize T-cell activation that was induced by activating intermediate half-life interactions. However, short TCR/pMHC interactions fail at promoting phosphorylation of signaling molecules at the T-cell-APC contact interface, which are needed for T-cell activation. Our data suggest that although intermediate half-life pMHC ligands promote assembly of activating synapses, this process can be inhibited by short half-life antagonistic pMHC ligands, which promote the assembly of non activating synapses.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Polaridad Celular , Complejo Mayor de Histocompatibilidad , Linfocitos T/inmunología , Animales , Células Presentadoras de Antígenos/citología , Línea Celular , Aparato de Golgi/ultraestructura , Sinapsis Inmunológicas/inmunología , Ligandos , Activación de Linfocitos/inmunología , Ratones , Ratones Endogámicos C57BL , Péptidos/inmunología , Linfocitos T/citologíaRESUMEN
Cytotoxic T lymphocytes (CTLs) are antigen-specific killer cells equipped to identify and eliminate host cells that have been altered through infection or transformation. Both chimeric antigen-receptor (CAR) T cell therapies and immune checkpoint blockade (ICB) therapies are based on successful elimination of tumor cells by cytotoxic effectors. In this opinion article, we outline cell-intrinsic mechanisms by which tumor cells defend against CTLs, highlighting pathways that confer resistance and proposing opportunities for combination therapies. We discuss how exogenous killing entities [e.g., supramolecular attack particles (SMAPs)] offer a novel strategy to circumvent cellular resistance mechanisms. Our opinion article highlights the importance of identifying, quantifying, and targeting tumor defense mechanisms at the interface between tumor cells and CTLs as a critical consideration in the development of immunotherapy approaches.
Asunto(s)
Neoplasias , Linfocitos T Citotóxicos , Humanos , Neoplasias/patología , Inmunoterapia , Células Asesinas Naturales , Inmunoterapia AdoptivaRESUMEN
CD8+ cytotoxic T lymphocytes (CTL) play a key role in anti-tumor immune response. They are therefore at the heart of current immunotherapy protocols against cancer. Despite current strategies to potentiate CTL responses, cancer cells can resist CTL attack, thus limiting the efficacy of immunotherapies. To optimize immunotherapy, it is urgent to develop rapid assays allowing to assess CTL-cancer cell confrontation at the lytic synapse.In this chapter, we describe a flow cytometry-based method to simultaneously assess the extent of CTL activation and of tumor cell reparative membrane turnover in CTL/target cell conjugates. Such a method can be performed using a limited number of cells. It can therefore be employed in clinical settings when only a few patient-derived cells might be available.
Asunto(s)
Antineoplásicos , Linfocitos T Citotóxicos , Humanos , Citotoxicidad Inmunológica , Linfocitos T CD8-positivos , Antineoplásicos/metabolismo , Membrana Celular , SinapsisRESUMEN
An unresolved issue in contemporary biomedicine is the overwhelming number and diversity of complex images that require annotation, analysis and interpretation. Recent advances in Deep Learning have revolutionized the field of computer vision, creating algorithms that compete with human experts in image segmentation tasks. However, these frameworks require large human-annotated datasets for training and the resulting "black box" models are difficult to interpret. In this study, we introduce Kartezio, a modular Cartesian Genetic Programming-based computational strategy that generates fully transparent and easily interpretable image processing pipelines by iteratively assembling and parameterizing computer vision functions. The pipelines thus generated exhibit comparable precision to state-of-the-art Deep Learning approaches on instance segmentation tasks, while requiring drastically smaller training datasets. This Few-Shot Learning method confers tremendous flexibility, speed, and functionality to this approach. We then deploy Kartezio to solve a series of semantic and instance segmentation problems, and demonstrate its utility across diverse images ranging from multiplexed tissue histopathology images to high resolution microscopy images. While the flexibility, robustness and practical utility of Kartezio make this fully explicable evolutionary designer a potential game-changer in the field of biomedical image processing, Kartezio remains complementary and potentially auxiliary to mainstream Deep Learning approaches.
Asunto(s)
Algoritmos , Procesamiento de Imagen Asistido por Computador , Humanos , Procesamiento de Imagen Asistido por Computador/métodos , Microscopía , Evolución Biológica , SemánticaRESUMEN
T-cell scanning for antigen-presenting cells (APC) is a finely tuned process. Whereas non-cognate APC trigger T-cell motility via chemokines and intercellular adhesion molecule-1 (ICAM-1), cognate APC deliver a stop signal resulting from antigen recognition. We tested in vitro the contribution of the actin cytoskeleton regulator Wiskott-Aldrich syndrome protein (WASP) to the scanning activity of primary human CD4(+) T cells. WASP knock-down resulted in increased T-cell motility upon encounter with non-cognate dendritic cells or B cells and reduced capacity to stop following antigen recognition. The high motility of WASP-deficient T cells was accompanied by a diminished ability to round up and to stabilize pauses. WASP-deficient T cells migrated in a normal proportion towards CXCL12, CCL19 and CCL21, but displayed an increased adhesion and elongation on ICAM-1. The elongated morphology of WASP-deficient T cells was related to a reduced confinement of high-affinity lymphocyte function-associated antigen 1 to the mid-cell zone. Our data therefore indicate that WASP controls CD4(+) T-cell motility upon APC encounter by regulating lymphocyte function-associated antigen 1 spatial distribution.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Linfocitos T CD4-Positivos/inmunología , Movimiento Celular , Molécula 1 de Adhesión Intercelular/inmunología , Proteína del Síndrome de Wiskott-Aldrich/inmunología , Linfocitos T CD4-Positivos/citología , Adhesión Celular , Células Cultivadas , Humanos , ARN Interferente Pequeño/genética , Proteína del Síndrome de Wiskott-Aldrich/genéticaRESUMEN
A key feature in T lymphocyte biology is that Th cells rapidly polarize their secretory machinery toward cognate APCs. The molecular mechanisms of these dynamic Th cell responses and their impact on APC biology remain to be elucidated. In this study, we demonstrate that protein kinase Czeta (PKCzeta) is rapidly activated at the immunological synapse (IS) in human Th cells interacting with cognate dendritic cells (DCs) and that a functional PKCzeta is required for the polarization of Th cell secretory machinery toward DCs. We also show that PKCzeta-dependent Th cell polarization allows dedicated delivery of IFN-gamma and CD40L at the IS and is required for the activation of cognate DCs to IL-12 production. PKCzeta synaptic activation is a low-threshold phenomenon and, in Th cells interacting with multiple DCs, selectively occurs at the IS formed with the DCs offering the strongest stimulus leading to dedicated Th cell polarization. Our results identify the PKCzeta signaling pathway as a key component of the Th cell polarization machinery and provide a molecular basis for T cell-dedicated activation of cognate DCs.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Células Presentadoras de Antígenos/metabolismo , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Polaridad Celular/inmunología , Sinapsis Inmunológicas/metabolismo , Activación de Linfocitos/inmunología , Proteína Quinasa C/metabolismo , Linfocitos T CD4-Positivos/enzimología , Ligando de CD40/metabolismo , Células Cultivadas , Técnicas de Cocultivo , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Activación Enzimática/inmunología , Humanos , Sinapsis Inmunológicas/enzimología , Sinapsis Inmunológicas/inmunología , Interferón gamma/metabolismo , Isoenzimas/metabolismo , Isoenzimas/fisiología , Fosforilación/inmunología , Proteína Quinasa C/fisiología , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Transducción de Señal/inmunologíaRESUMEN
CD8+ cytotoxic T lymphocytes (CTLs) are the main cellular effectors of the adaptive immune response against cancer cells, which in turn have evolved sophisticated cellular defense mechanisms to withstand CTL attack. Herein we provide a critical review of the pertinent literature on early and late attack/defense events taking place at the CTL/target cell lytic synapse. We examine the earliest steps of CTL-mediated cytotoxicity ("the poison arrows") elicited within seconds of CTL/target cell encounter, which face commensurately rapid synaptic repair mechanisms on the tumor cell side, providing the first formidable barrier to CTL attack. We examine how breach of this first defensive barrier unleashes the inextinguishable "Greek fire" in the form of granzymes whose broad cytotoxic potential is linked to activation of cell death executioners, injury of vital organelles, and destruction of intracellular homeostasis. Herein tumor cells deploy slower but no less sophisticated defensive mechanisms in the form of enhanced autophagy, increased reparative capacity, and dysregulation of cell death pathways. We discuss how the newly discovered supra-molecular attack particles (SMAPs, the "scorpion bombs"), seek to overcome the robust defensive mechanisms that confer tumor cell resistance. Finally, we discuss the implications of the aforementioned attack/defense mechanisms on the induction of regulated cell death (RCD), and how different contemporary RCD modalities (including apoptosis, pyroptosis, and ferroptosis) may have profound implications for immunotherapy. Thus, we propose that understanding and targeting multiple steps of the attack/defense process will be instrumental to enhance the efficacy of CTL anti-tumor activity and meet the outstanding challenges in clinical immunotherapy.