RESUMEN
To mount an immune response, T cells must first find rare antigens present at the surface of antigen-presenting cells (APCs). They achieve this by migrating rapidly through the crowded space of tissues and constantly sampling the surface of APCs. Upon antigen recognition, T cells decelerate and polarise towards the APC, ultimately forming a specialised interface known as the immunological synapse. These conjugates form as the result of the interaction between pairs of receptors/ligands that are under mechanical stress due to the continuously reorganising cell cytoskeleton. In this review, we discuss the involvement of mechanical forces during antigen recognition by migrating T cells. We will explore this question from a conceptual and technical perspective, with the aim of providing new insights into the emerging field of mechanobiology.
Asunto(s)
Células Presentadoras de Antígenos/inmunología , Antígenos/inmunología , Linfocitos T/citología , Linfocitos T/inmunología , Fenómenos Biofísicos , HumanosRESUMEN
Dendritic cells (DCs) patrol their environment by linking antigen acquisition by macropinocytosis to cell locomotion. DC activation upon bacterial sensing inhibits macropinocytosis and increases DC migration, thus promoting the arrival of DCs to lymph nodes for antigen presentation to T cells. The signaling events that trigger such changes are not fully understood. We show that lysosome signaling plays a critical role in this process. Upon bacterial sensing, lysosomal calcium is released by the ionic channel TRPML1 (transient receptor potential cation channel, mucolipin subfamily, member 1), which activates the actin-based motor protein myosin II at the cell rear, promoting fast and directional migration. Lysosomal calcium further induces the activation of the transcription factor EB (TFEB), which translocates to the nucleus to maintain TRPML1 expression. We found that the TRPML1-TFEB axis results from the down-regulation of macropinocytosis after bacterial sensing by DCs. Lysosomal signaling therefore emerges as a hitherto unexpected link between macropinocytosis, actomyosin cytoskeleton organization, and DC migration.
Asunto(s)
Movimiento Celular , Células Dendríticas/inmunología , Lisosomas/metabolismo , Transducción de Señal , Animales , Presentación de Antígeno , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/genética , Factores de Transcripción Básicos con Cremalleras de Leucinas y Motivos Hélice-Asa-Hélice/metabolismo , Calcio/metabolismo , Diferenciación Celular , Núcleo Celular/metabolismo , Citoesqueleto/metabolismo , Células Dendríticas/fisiología , Regulación hacia Abajo , Lisosomas/inmunología , Ratones , Miosina Tipo II/genética , Miosina Tipo II/metabolismo , Pinocitosis , Canales de Potencial de Receptor Transitorio/deficiencia , Canales de Potencial de Receptor Transitorio/genética , Canales de Potencial de Receptor Transitorio/metabolismoRESUMEN
Cell migration is a hallmark of dendritic cells (DCs) function. It is needed for DCs to scan their environment in search for antigens as well as to reach lymphatic organs in order to trigger T lymphocyte's activation. Such interaction leads to tolerance in the case of DCs migrating under homeostatic conditions or to immunity in the case of DCs migrating upon encounter with pathogen-associated molecular patterns. Cell migration is therefore essential for DCs to transfer information from peripheral tissues to lymphoid organs, thereby linking innate to adaptive immunity. This stresses the need to unravel the molecular mechanisms involved. However, the tremendous complexity of the tissue microenvironment as well as the limited spatio-temporal resolution of in vivo imaging techniques has made this task difficult. To bypass this problem, we have developed microfabrication-based experimental tools that are compatible with high-resolution imaging. Here, we will discuss how such devices can be used to study DC migration under controlled conditions that mimic their physiological environment in a robust quantitative manner.
Asunto(s)
Microambiente Celular , Quimiotaxis , Células Dendríticas/inmunología , Microscopía , Microtecnología , Inmunidad Adaptativa , Animales , Polaridad Celular , Citocinas/inmunología , Citocinas/metabolismo , Células Dendríticas/metabolismo , Diseño de Equipo , Humanos , Inmunidad Innata , Microscopía/instrumentación , Microscopía/métodos , Microtecnología/instrumentación , Microtecnología/métodos , Miniaturización , Fenotipo , Transducción de Señal , Factores de TiempoRESUMEN
Dendritic cell (DC) migration in peripheral tissues serves two main functions: antigen sampling by immature DCs, and chemokine-guided migration towards lymphatic vessels (LVs) on maturation. These migratory events determine the efficiency of the adaptive immune response. Their regulation by the core cell locomotion machinery has not been determined. Here, we show that the migration of immature DCs depends on two main actin pools: a RhoA-mDia1-dependent actin pool located at their rear, which facilitates forward locomotion; and a Cdc42-Arp2/3-dependent actin pool present at their front, which limits migration but promotes antigen capture. Following TLR4-MyD88-induced maturation, Arp2/3-dependent actin enrichment at the cell front is markedly reduced. Consequently, mature DCs switch to a faster and more persistent mDia1-dependent locomotion mode that facilitates chemotactic migration to LVs and lymph nodes. Thus, the differential use of actin-nucleating machineries optimizes the migration of immature and mature DCs according to their specific function.
Asunto(s)
Actinas/metabolismo , Diferenciación Celular/fisiología , Movimiento Celular/fisiología , Quimiotaxis/fisiología , Células Dendríticas/metabolismo , Animales , Células Cultivadas , RatonesRESUMEN
The immune response relies on the migration of leukocytes and on their ability to stop in precise anatomical locations to fulfil their task. How leukocyte migration and function are coordinated is unknown. Here we show that in immature dendritic cells, which patrol their environment by engulfing extracellular material, cell migration and antigen capture are antagonistic. This antagonism results from transient enrichment of myosin IIA at the cell front, which disrupts the back-to-front gradient of the motor protein, slowing down locomotion but promoting antigen capture. We further highlight that myosin IIA enrichment at the cell front requires the MHC class II-associated invariant chain (Ii). Thus, by controlling myosin IIA localization, Ii imposes on dendritic cells an intermittent antigen capture behaviour that might facilitate environment patrolling. We propose that the requirement for myosin II in both cell migration and specific cell functions may provide a general mechanism for their coordination in time and space.
Asunto(s)
Antígenos de Diferenciación de Linfocitos B/metabolismo , Antígenos/metabolismo , Movimiento Celular/fisiología , Células Dendríticas/metabolismo , Antígenos de Histocompatibilidad Clase II/metabolismo , Miosina Tipo II/metabolismo , Ovalbúmina/metabolismo , Animales , Antígenos de Diferenciación de Linfocitos B/genética , Células de la Médula Ósea , Catepsinas/genética , Catepsinas/metabolismo , Femenino , Antígenos de Histocompatibilidad Clase II/genética , Masculino , Ratones , Técnicas Analíticas Microfluídicas , Miosina Tipo II/genéticaRESUMEN
Dendritic cells (DCs) constitute a complex cell population that resides in both peripheral tissues and lymphoid organs. Their major function in tissues is to patrol their environment in search of danger-associated antigens to transport to lymph nodes and present to T lymphocytes. This process constitutes the first step of the adaptive immune response and relies on specific DC properties, including a high endocytic capacity as well as efficient motility in confined three-dimensional environments. Although cell motility has been widely studied, little is known on how the geometric characteristics of the environment influence DC migration and function. In this review, we give an overview of the basic physical principles and molecular mechanisms that control DC migration under confinement and discuss how such mechanisms impact the environment-patrolling capacity of DCs.
Asunto(s)
Movimiento Celular/inmunología , Células Dendríticas/fisiología , Animales , Antígenos/inmunología , HumanosRESUMEN
HIV-1-infected macrophages likely represent viral reservoirs, as they accumulate newly formed virions in internal virus-containing compartments (VCCs). However, the nature and biogenesis of VCCs remain poorly defined. We show that upon HIV-1 infection of primary human macrophages, Gag is recruited to preexisting compartments containing the scavenger receptor CD36, which then become VCCs. Silencing of CD36 in HIV-1-infected macrophages decreases the amount of virions released. Strikingly, soluble anti-CD36 antibodies, but not the natural ligands of CD36, inhibit release of virions from HIV-1-infected macrophages and the transmission of virus to CD4(+) T cells. The effect of the antibodies is potent, rapid, and induces the retention of virions within VCCs. Ectopic expression of CD36 in HeLa cells renders them susceptible to the inhibitory effect of the anti-CD36 mAb upon HIV-1 infection. We show that the anti-CD36 mAb inhibits HIV-1 release by clustering newly formed virions at their site of budding, and that signaling via CD36 is not required. Thus, HIV-1 reservoirs in macrophages may be tackled therapeutically using anti-CD36 antibodies to prevent viral dissemination.