Examinando por Autor "Lladser, A."

Mostrando 1 - 3 de 3
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    Ítem
    Caveolin-1 expression increases upon maturation in dendritic cells and promotes their migration to lymph nodes thereby favoring the induction of CD8+ T cell responses
    (Frontiers Media, 2017-12) Oyarce, C.; Cruz-Gomez, S.; Galvez-Cancino, F.; Vargas, P.; Moreau, H.D.; Diaz-Valdivia, N.; Diaz, J.; Salazar-Onfray, F.A.; Pacheco, R.; Lennon-Dumenil, A.M.; Quest, A.F.G.; Lladser, A.
    Dendritic cell (DC) trafficking from peripheral tissues to lymph nodes (LNs) is a key step required to initiate T cell responses against pathogens as well as tumors. In this context, cellular membrane protrusions and the actin cytoskeleton are essential to guide DC migration towards chemotactic signals. Caveolin-1 (CAV1) is a scaffolding protein that modulates signaling pathways leading to remodeling of the actin cytoskeleton and enhanced migration of cancer cells. However, whether CAV1 is relevant for DC function and specifically for DC migration to LNs is unknown. Here, we show that CAV1 expression is upregulated in DCs upon LPS- and TNF-a-induced maturation. CAV1 deficiency did not affect differentiation, maturation, or the ability of DCs to activate CD8+ T cells in vitro. However, CAV1-deficient (CAV1-/-) DCs displayed reduced in vivo trafficking to draining LNs in control and inflammatory conditions. In vitro, CAV1-/- DCs showed reduced directional migration in CCL21 gradients in transwell assays without affecting migration velocity in confined microchannels or three-dimensional collagen matrices. In addition, CAV1-/- DCs displayed reduced activation of the small GTPase Rac1, a regulator of actin cytoskeletal remodeling, and lower numbers of F-actin-forming protrusions. Furthermore, mice adoptively transferred with peptide-pulsed CAV1-/- DCs showed reduced CD8+ T cell responses and antitumor protection. Our results suggest that CAV1 promotes the activation of Rac1 and the formation of membrane protrusions that favor DC chemotactic trafficking toward LNs where they can initiate cytotoxic T cell responses.
  • Miniatura
    Ítem
    Dopaminergic stimulation of myeloid antigen-presenting cells attenuates signal transducer and activator of transcription 3-activation favouring the development of experimental autoimmune encephalomyelitis
    (Frontiers Media, 2018-03) Prado, C.; Gaiazzi, M.; González, H.; Ugalde, V.; Figueroa, A.; Osorio-Barrios, F.J.; López, E.; Lladser, A.; Rasini, E.; Marino, F.; Zaffaroni, M.; Cosentino, M.; Pacheco, R.
    The dual potential to promote tolerance or inflammation to self-antigens makes dendritic cells (DCs) fundamental players in autoimmunity. Previous results have shown that stimulation of dopamine receptor D5 (DRD5) in DCs potentiates their inflammatory behaviour, favouring the development of experimental autoimmune encephalomyelitis (EAE). Here, we aimed to decipher the underlying mechanism and to test its relevance in multiple sclerosis (MS) patients. Our data shows that DRD5-deficiency confined to DCs in EAE mice resulted in reduced frequencies of CD4+ T-cell subsets with inflammatory potential in the central nervous system, including not only Th1 and Th17 cells but also granulocyte-macrophage colony-stimulating factor producers. Importantly, ex vivo depletion of dopamine from DCs resulted in a dramatic reduction of EAE severity, highlighting the relevance of an autocrine loop promoting inflammation in vivo. Mechanistic analyses indicated that DRD5-signalling in both mouse DCs and human monocytes involves the attenuation of signal transducer and activator of transcription 3-activation, a transcription factor that limits the production of the inflammatory cytokines interleukin (IL)-12 and IL-23. Furthermore, we found an exacerbated expression of all dopamine receptors in peripheral blood pro-inflammatory monocytes obtained from MS patients. These findings illustrate a novel mechanism by which myeloid antigen-presenting cells may trigger the onset of their inflammatory behaviour promoting the development of autoimmunity. © 2018 Prado, Gaiazzi, González, Ugalde, Figueroa, Osorio-Barrios, López, Lladser, Rasini, Marino, Zaffaroni, Cosentino and Pacheco.
  • Miniatura
    Ítem
    In vitro-generated Tc17 cells present a memory phenotype and serve as a reservoir of Tc1 cells in vivo
    (Frontiers Media, 2018-02) Flores-Santibáñez, F.; Cuadra, B.; Fernández, D.; Rosemblatt, M.V.; Núñez, S.; Cruz, P.; Gálvez-Cancino, F.; César Cárdenas, J.; Lladser, A.; Rosemblatt, M.; Bono, M.R.; Sauma, D.
    Memory CD8+ T cells are ideal candidates for cancer immunotherapy because they can mediate long-term protection against tumors. However, the therapeutic potential of different in vitro-generated CD8+ T cell effector subsets to persist and become memory cells has not been fully characterized. Type 1 CD8+ T (Tc1) cells produce interferon-γ and are endowed with high cytotoxic capacity, whereas IL-17-producing CD8+ T (Tc17) cells are less cytotoxic but display enhanced self-renewal capacity. We sought to evaluate the functional properties of in vitro-generated Tc17 cells and elucidate their potential to become long lasting memory cells. Our results show that in vitro-generated Tc17 cells display a greater in vivo persistence and expansion in response to secondary antigen stimulation compared to Tc1 cells. When transferred into recipient mice, Tc17 cells persist in secondary lymphoid organs, present a recirculation behavior consistent with central memory T cells, and can shift to a Tc1 phenotype. Accordingly, Tc17 cells are endowed with a higher mitochondrial spare respiratory capacity than Tc1 cells and express higher levels of memory-related molecules than Tc1 cells. Together, these results demonstrate that in vitro-generated Tc17 cells acquire a central memory program and provide a lasting reservoir of Tc1 cells in vivo, thus supporting the use of Tc17 lymphocytes in the design of novel and more effective therapies.