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Support for basic science has been eclipsed by initiatives aimed at specific medical problems. The latest example is the dismantling of the Skirball Institute at NYU School of Medicine. Here, we reflect on the achievements and mission underlying the Skirball to gain insight into the dividends of maintaining a basic science vision within the academic enterprises.
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Academias e Institutos , Investigación Biomédica , Facultades de MedicinaRESUMEN
Cancer remains one of the leading causes of mortality worldwide, leading to increased interest in utilizing immunotherapy strategies for better cancer treatments. In the past decade, CD103+ T cells have been associated with better clinical prognosis in patients with cancer. However, the specific immune mechanisms contributing toward CD103-mediated protective immunity remain unclear. Here, we show an unexpected and transient CD61 expression, which is paired with CD103 at the synaptic microclusters of T cells. CD61 colocalization with the T cell antigen receptor further modulates downstream T cell antigen receptor signaling, improving antitumor cytotoxicity and promoting physiological control of tumor growth. Clinically, the presence of CD61+ tumor-infiltrating T lymphocytes is associated with improved clinical outcomes, mediated through enhanced effector functions and phenotype with limited evidence of cellular exhaustion. In conclusion, this study identified an unconventional and transient CD61 expression and pairing with CD103 on human immune cells, which potentiates a new target for immune-based cellular therapies.
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Antígenos CD , Apirasa , Cadenas alfa de Integrinas , Receptores de Antígenos de Linfocitos T , Transducción de Señal , Animales , Humanos , Ratones , Antígenos CD/metabolismo , Antígenos CD/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica , Cadenas alfa de Integrinas/metabolismo , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Transducción de Señal/inmunología , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Germinal center (GC) B cells undergo proliferation at very high rates in a hypoxic microenvironment but the cellular processes driving this are incompletely understood. Here we show that the mitochondria of GC B cells are highly dynamic, with significantly upregulated transcription and translation rates associated with the activity of transcription factor A, mitochondrial (TFAM). TFAM, while also necessary for normal B cell development, is required for entry of activated GC precursor B cells into the germinal center reaction; deletion of Tfam significantly impairs GC formation, function and output. Loss of TFAM in B cells compromises the actin cytoskeleton and impairs cellular motility of GC B cells in response to chemokine signaling, leading to their spatial disorganization. We show that B cell lymphoma substantially increases mitochondrial translation and that deletion of Tfam in B cells is protective against the development of lymphoma in a c-Myc transgenic mouse model. Finally, we show that pharmacological inhibition of mitochondrial transcription and translation inhibits growth of GC-derived human lymphoma cells and induces similar defects in the actin cytoskeleton.
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Linfoma de Células B , Linfoma , Ratones , Humanos , Animales , Linfocitos B/patología , Centro Germinal/patología , Transcripción Genética , Linfoma de Células B/genética , Linfoma de Células B/patología , Ratones Transgénicos , Microambiente TumoralRESUMEN
One of the 2019 Canada Gairdner International Awards recognizes Timothy Springer's discovery of the first immune system adhesion molecules involved in lymphocyte homing and the translation of those discoveries into therapeutics for autoimmune disease and cancer.
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Adhesión Celular/fisiología , Integrinas/metabolismo , Linfocitos T/metabolismo , Citoesqueleto de Actina , Anticuerpos Monoclonales/inmunología , Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/terapia , Humanos , Glicoproteínas de Membrana/metabolismo , Neoplasias/inmunología , Neoplasias/terapia , Selectina-P/metabolismo , Linfocitos T/inmunologíaRESUMEN
The CD2-CD58 recognition system promotes adhesion and signaling and counters exhaustion in human T cells. We found that CD2 localized to the outer edge of the mature immunological synapse, with cellular or artificial APC, in a pattern we refer to as a 'CD2 corolla'. The corolla captured engaged CD28, ICOS, CD226 and SLAM-F1 co-stimulators. The corolla amplified active phosphorylated Src-family kinases (pSFK), LAT and PLC-γ over T cell receptor (TCR) alone. CD2-CD58 interactions in the corolla boosted signaling by 77% as compared with central CD2-CD58 interactions. Engaged PD-1 invaded the CD2 corolla and buffered CD2-mediated amplification of TCR signaling. CD2 numbers and motifs in its cytoplasmic tail controlled corolla formation. CD8+ tumor-infiltrating lymphocytes displayed low expression of CD2 in the majority of people with colorectal, endometrial or ovarian cancer. CD2 downregulation may attenuate antitumor T cell responses, with implications for checkpoint immunotherapies.
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Antígenos CD2/metabolismo , Antígenos CD58/metabolismo , Linfocitos T CD8-positivos/metabolismo , Sinapsis Inmunológicas/metabolismo , Linfocitos Infiltrantes de Tumor/metabolismo , Neoplasias/metabolismo , Receptor de Muerte Celular Programada 1/metabolismo , Adhesión Celular , Células Cultivadas , Humanos , Tolerancia Inmunológica , Activación de Linfocitos , Unión Proteica , Receptor Cross-Talk , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Análisis de la Célula IndividualRESUMEN
T cell activation and function require a structured engagement of antigen-presenting cells. These cell contacts are characterized by two distinct dynamics in vivo: transient contacts resulting from promigratory junctions called immunological kinapses or prolonged contacts from stable junctions called immunological synapses. Kinapses operate in the steady state to allow referencing to self-peptide-MHC (pMHC) and searching for pathogen-derived pMHC. Synapses are induced by T cell receptor (TCR) interactions with agonist pMHC under specific conditions and correlate with robust immune responses that generate effector and memory T cells. High-resolution imaging has revealed that the synapse is highly coordinated, integrating cell adhesion, TCR recognition of pMHC complexes, and an array of activating and inhibitory ligands to promote or prevent T cell signaling. In this review, we examine the molecular components, geometry, and timing underlying kinapses and synapses. We integrate recent molecular and physiological data to provide a synthesis and suggest ways forward.
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Sinapsis Inmunológicas/inmunología , Activación de Linfocitos , Linfocitos T/inmunología , Animales , Comunicación Celular , Humanos , Sinapsis Inmunológicas/metabolismo , Receptores de Antígenos de Linfocitos T/inmunología , Receptores de Antígenos de Linfocitos T/metabolismo , Transducción de Señal , Linfocitos T/citología , Linfocitos T/metabolismoRESUMEN
Important signaling events at the immunological synapse have increasingly been linked to cis interactions between receptors on T cells. In this issue of Immunity, Zhao et al.1 implicate cis CD28/B7 interactions facilitated by curved membrane invaginations in boosting tumor immunity.
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Antígenos CD28 , Endocitosis , Sinapsis Inmunológicas , Transducción de SeñalRESUMEN
Cell-cell interfaces are found throughout multicellular organisms, from transient interactions between motile immune cells to long-lived cell-cell contacts in epithelia. Studies of immune cell interactions, epithelial cell barriers, neuronal contacts and sites of cell-cell fusion have identified a core set of features shared by cell-cell interfaces that critically control their function. Data from diverse cell types also show that cells actively and passively regulate the localization, strength, duration and cytoskeletal coupling of receptor interactions governing cell-cell signalling and physical connections between cells, indicating that cell-cell interfaces have a unique membrane organization that emerges from local molecular and cellular mechanics. In this Review, we discuss recent findings that support the emerging view of cell-cell interfaces as specialized compartments that biophysically constrain the arrangement and activity of their protein, lipid and glycan components. We also review how these biophysical features of cell-cell interfaces allow cells to respond with high selectivity and sensitivity to multiple inputs, serving as the basis for wide-ranging cellular functions. Finally, we consider how the unique properties of cell-cell interfaces present opportunities for therapeutic intervention.
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Comunicación Celular/fisiología , Compartimento Celular/fisiología , Fenómenos Fisiológicos Celulares/fisiología , Animales , Fusión Celular , Células Epiteliales/citología , Células Epiteliales/fisiología , Humanos , Mecanotransducción Celular/fisiología , Neuronas/citología , Neuronas/fisiologíaRESUMEN
Inflammation is paramount in pancreatic oncogenesis. We identified a uniquely activated γδT cell population, which constituted â¼40% of tumor-infiltrating T cells in human pancreatic ductal adenocarcinoma (PDA). Recruitment and activation of γδT cells was contingent on diverse chemokine signals. Deletion, depletion, or blockade of γδT cell recruitment was protective against PDA and resulted in increased infiltration, activation, and Th1 polarization of αßT cells. Although αßT cells were dispensable to outcome in PDA, they became indispensable mediators of tumor protection upon γδT cell ablation. PDA-infiltrating γδT cells expressed high levels of exhaustion ligands and thereby negated adaptive anti-tumor immunity. Blockade of PD-L1 in γδT cells enhanced CD4(+) and CD8(+) T cell infiltration and immunogenicity and induced tumor protection suggesting that γδT cells are critical sources of immune-suppressive checkpoint ligands in PDA. We describe γδT cells as central regulators of effector T cell activation in cancer via novel cross-talk.
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Carcinogénesis/inmunología , Carcinoma Ductal Pancreático/inmunología , Carcinoma Ductal Pancreático/fisiopatología , Activación de Linfocitos/inmunología , Linfocitos T/inmunología , Inmunidad Adaptativa , Animales , Carcinogénesis/patología , Células Cultivadas , Quimiocinas/inmunología , Células Epiteliales/fisiología , Femenino , Humanos , Ligandos , Masculino , Ratones , Ratones Endogámicos C57BL , Transducción de Señal/inmunología , Microambiente Tumoral/inmunologíaRESUMEN
Foxo transcription factors play an essential role in regulating specialized lymphocyte functions and in maintaining T cell quiescence. Here, we used a system in which Foxo1 transcription-factor activity, which is normally terminated upon cell activation, cannot be silenced, and we show that enforcing Foxo1 activity disrupts homeostasis of CD4 conventional and regulatory T cells. Despite limiting cell metabolism, continued Foxo1 activity is associated with increased activation of the kinase Akt and a cell-intrinsic proliferative advantage; however, survival and cell division are decreased in a competitive setting or growth-factor-limiting conditions. Via control of expression of the transcription factor Myc and the IL-2 receptor ß-chain, termination of Foxo1 signaling couples the increase in cellular cholesterol to biomass accumulation after activation, thereby facilitating immunological synapse formation and mTORC1 activity. These data reveal that Foxo1 regulates the integration of metabolic and mitogenic signals essential for T cell competitive fitness and the coordination of cell growth with cell division.
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Linfocitos T CD4-Positivos/fisiología , Proteína Forkhead Box O1/metabolismo , Linfocitos T Reguladores/fisiología , Animales , Proliferación Celular , Células Cultivadas , Colesterol/metabolismo , Proteína Forkhead Box O1/genética , Perfilación de la Expresión Génica , Homeostasis , Sinapsis Inmunológicas/metabolismo , Subunidad beta del Receptor de Interleucina-2/genética , Subunidad beta del Receptor de Interleucina-2/metabolismo , Activación de Linfocitos , Diana Mecanicista del Complejo 1 de la Rapamicina/metabolismo , Ratones , Ratones Noqueados , Proteínas Proto-Oncogénicas c-akt/metabolismo , Proteínas Proto-Oncogénicas c-myc/genética , Proteínas Proto-Oncogénicas c-myc/metabolismo , Transducción de SeñalRESUMEN
Human mutations in neuropeptide Y (NPY) have been linked to high body mass index but not altered dietary patterns1. Here we uncover the mechanism by which NPY in sympathetic neurons2,3 protects from obesity. Imaging of cleared mouse brown and white adipose tissue (BAT and WAT, respectively) established that NPY+ sympathetic axons are a smaller subset that mostly maps to the perivasculature; analysis of single-cell RNA sequencing datasets identified mural cells as the main NPY-responsive cells in adipose tissues. We show that NPY sustains the proliferation of mural cells, which are a source of thermogenic adipocytes in both BAT and WAT4-6. We found that diet-induced obesity leads to neuropathy of NPY+ axons and concomitant depletion of mural cells. This defect was replicated in mice with NPY abrogated from sympathetic neurons. The loss of NPY in sympathetic neurons whitened interscapular BAT, reducing its thermogenic ability and decreasing energy expenditure before the onset of obesity. It also caused adult-onset obesity of mice fed on a regular chow diet and rendered them more susceptible to diet-induced obesity without increasing food consumption. Our results indicate that, relative to central NPY, peripheral NPY produced by sympathetic nerves has the opposite effect on body weight by sustaining energy expenditure independently of food intake.
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T cells express a somatically recombined antigen receptor (αßTCR) that is calibrated during development to respond to changes in peptides displayed by major histocompatibility complex proteins (pMHC) on the surface of antigen-presenting cells (APC). A key characteristic of pMHC for adaptive immunity is the ability to sample internal states of cells and tissues to sensitively detect changes associated with infection, cell derangement, or tissue injury. Physical T cell-APC contact sets up an axis for polarization of TCR, adhesion molecules, kinases, cytoskeletal elements, and organelles inherent in this mode of juxtacrine signaling. The discovery of further lateral organization of the TCR and adhesion molecules into radially symmetric compartments, the immunological synapse, revealed an intersecting plane of symmetry and potential for regulated symmetry breaking to control duration of T cell-APC interactions. In addition to organizing signaling machinery, the immunological synapse directs the polarized transport and secretion of cytokines and cytolytic agents across the synaptic cleft and is a site for the generation and exocytic release of bioactive microvesicles that can functionally affect recipient APC and other cells in the environment. This machinery is coopted by retroviruses, and human immune deficiency virus-1 may even use antigen-specific synapses for infection of healthy T cells. Here, we discuss recent advances in the molecular and cell biological mechanisms of immunological synapse assembly and signaling and its role in intercellular communication across the synaptic cleft.
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Comunicación Celular , Sinapsis Inmunológicas/metabolismo , Transducción de Señal , Linfocitos T/citología , Linfocitos T/metabolismo , Animales , Citoesqueleto/metabolismo , Infecciones por VIH/patología , HumanosRESUMEN
Understanding cellular decisions due to receptor-ligand interactions at cell-cell interfaces has been hampered by the difficulty of independently varying the surface density of multiple different ligands. Here, we express the synthetic binder protein SpyCatcher, designed to form spontaneous covalent bonds with interactors carrying a Spytag, on the cell surface. Using this, we show that addition of different concentrations and combinations of native Spytag-fused ligands allows for the combinatorial display of ligands on cells within minutes. We use this combinatorial display of cell surface ligands-called CombiCells-to assess T cell antigen sensitivity and the impact of T cell co-stimulation and co-inhibition receptors. We find that the T cell receptor (TCR) displayed greater sensitivity to peptides on major-histocompatibility complexes (pMHC) than synthetic chimeric antigen receptor (CARs) and bi-specific T cell engager (BiTEs) display to their target antigen, CD19. While TCR sensitivity was greatly enhanced by CD2/CD58 interactions, CAR sensitivity was primarily but more modestly enhanced by LFA-1/ICAM-1 interactions. Lastly, we show that PD-1/PD-L1 engagement inhibited T cell activation triggered solely by TCR/pMHC interactions, as well as the amplified activation induced by CD2 and CD28 co-stimulation. The ability to easily produce cells with different concentrations and combinations of ligands should accelerate the study of receptor-ligand interactions at cell-cell interfaces.
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Antígenos , Linfocitos T , Ligandos , Receptores de Antígenos de Linfocitos T/metabolismo , Activación de LinfocitosRESUMEN
Invariant Vγ9Vδ2 T cells respond to "phosphoantigen" metabolites through binding to the B30.2 domain of butyrophilin BTN3A. Yang et al. (2019) use molecular dynamic simulations based on X-ray structures of distinct B30.2 domain dimers to identify the asymmetric dimer as most active, which has implications for the inside-out signaling mechanism.
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Antígenos CD , Activación de Linfocitos , Butirofilinas , Linfocitos T/inmunología , Rayos XRESUMEN
The tumor necrosis factor receptor superfamily member HVEM is one of the most frequently mutated surface proteins in germinal center (GC)-derived B cell lymphomas. We found that HVEM deficiency increased B cell competitiveness during pre-GC and GC responses. The immunoglobulin (Ig) superfamily protein BTLA regulated HVEM-expressing B cell responses independently of B-cell-intrinsic signaling via HVEM or BTLA. BTLA signaling into T cells through the phosphatase SHP1 reduced T cell receptor (TCR) signaling and preformed CD40 ligand mobilization to the immunological synapse, thus diminishing the help delivered to B cells. Moreover, T cell deficiency in BTLA cooperated with B cell Bcl-2 overexpression, leading to GC B cell outgrowth. These results establish that HVEM restrains the T helper signals delivered to B cells to influence GC selection outcomes, and they suggest that BTLA functions as a cell-extrinsic suppressor of GC B cell lymphomagenesis.
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Linfocitos B/inmunología , Centro Germinal/inmunología , Proteínas Proto-Oncogénicas c-bcl-2/metabolismo , Receptores Inmunológicos/metabolismo , Miembro 14 de Receptores del Factor de Necrosis Tumoral/metabolismo , Linfocitos T Colaboradores-Inductores/inmunología , Animales , Proliferación Celular , Sinapsis Inmunológicas , Activación de Linfocitos , Ratones , Ratones Noqueados , Ratones Transgénicos , Comunicación Paracrina , Proteína Tirosina Fosfatasa no Receptora Tipo 6/metabolismo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores Inmunológicos/genética , Transducción de SeñalRESUMEN
The Plasmodium species that cause malaria are obligate intracellular parasites, and disease symptoms occur when these parasites replicate in human blood. Despite the risk of immune detection, the parasite delivers proteins that bind to host receptors on the cell surfaces of infected erythrocytes. In the causative parasite of the most deadly form of malaria in humans, Plasmodium falciparum, RIFINs form the largest family of surface proteins displayed by erythrocytes1. Some RIFINs can bind to inhibitory immune receptors, and these RIFINs act as targets for unusual antibodies that contain a LAIR1 ectodomain2-4 or as ligands for LILRB15. RIFINs stimulate the activation of and signalling by LILRB15, which could potentially lead to the dampening of human immune responses. Here, to understand how RIFINs activate LILRB1-mediated signalling, we determine the structure of a RIFIN bound to LILRB1. We show that this RIFIN mimics the natural activating ligand of LILRB1, MHC class I, in its LILRB1-binding mode. A single mutation in the RIFIN disrupts the complex, blocks LILRB1 binding of all tested RIFINs and abolishes signalling in a reporter assay. In a supported lipid bilayer system, which mimics the activation of natural killer (NK) cells by antibody-dependent cell-mediated cytotoxicity, both RIFIN and MHC are recruited to the immunological synapse of NK cells and reduce the activation of NK cells, as measured by the mobilization of perforin. Therefore, LILRB1-binding RIFINs mimic the binding mode of the natural ligand of LILRB1 and suppress the function of NK cells.
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Receptor Leucocitario Tipo Inmunoglobulina B1/química , Receptor Leucocitario Tipo Inmunoglobulina B1/inmunología , Malaria Falciparum/inmunología , Proteínas de la Membrana/química , Proteínas de la Membrana/inmunología , Proteínas Protozoarias/química , Proteínas Protozoarias/inmunología , Secuencia de Aminoácidos , Animales , Citotoxicidad Celular Dependiente de Anticuerpos/inmunología , Sitios de Unión/inmunología , Antígenos de Histocompatibilidad Clase I/inmunología , Humanos , Células Asesinas Naturales/citología , Células Asesinas Naturales/inmunología , Receptor Leucocitario Tipo Inmunoglobulina B1/metabolismo , Ligandos , Membrana Dobles de Lípidos , Activación de Linfocitos , Malaria Falciparum/parasitología , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Modelos Moleculares , Imitación Molecular/inmunología , Mutación , Perforina/metabolismo , Proteínas Protozoarias/genética , Proteínas Protozoarias/metabolismo , Transducción de SeñalRESUMEN
In circulation, T cells are spherical with selectin enriched dynamic microvilli protruding from the surface. Following extravasation, these microvilli serve another role, continuously surveying their environment for antigen in the form of peptide-MHC (pMHC) expressed on the surface of antigen presenting cells (APCs). Upon recognition of their cognate pMHC, the microvilli are initially stabilized and then flatten into F-actin dependent microclusters as the T cell spreads over the APC. Within 1-5 min, clathrin is recruited by the ESCRT-0 component Hrs to mediate release of T cell receptor (TCR) loaded vesicles directly from the plasma membrane by clathrin and ESCRT-mediated ectocytosis (CEME). After 5-10 min, Hrs is displaced by the endocytic clathrin adaptor epsin-1 to induce clathrin-mediated trans-endocytosis (CMTE) of TCR-pMHC conjugates. Here we discuss some of the functional properties of the clathrin machinery which enables it to control these topologically opposite modes of membrane transfer at the immunological synapse, and how this might be regulated during T cell activation.
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Clatrina , Linfocitos T , Clatrina/metabolismo , Células Presentadoras de Antígenos/metabolismo , Receptores de Antígenos de Linfocitos T , Endocitosis/fisiología , Complejos de Clasificación Endosomal Requeridos para el Transporte/metabolismo , ComunicaciónRESUMEN
Ligation of T cell receptor (TCR) to peptide-MHC (pMHC) complexes initiates signaling leading to T cell activation and TCR ubiquitination. Ubiquitinated TCR is then either internalized by the T cell or released toward the antigen-presenting cell (APC) in extracellular vesicles. How these distinct fates are orchestrated is unknown. Here, we show that clathrin is first recruited to TCR microclusters by HRS and STAM2 to initiate release of TCR in extracellular vesicles through clathrin- and ESCRT-mediated ectocytosis directly from the plasma membrane. Subsequently, EPN1 recruits clathrin to remaining TCR microclusters to enable trans-endocytosis of pMHC-TCR conjugates from the APC. With these results, we demonstrate how clathrin governs bidirectional membrane exchange at the immunological synapse through two topologically opposite processes coordinated by the sequential recruitment of ecto- and endocytic adaptors. This provides a scaffold for direct two-way communication between T cells and APCs.