Correction: critical role for sec22b-dependent antigen cross-presentation in antitumor immunity

The authors regret that in the original version of their paper, they mistakenly used the phrase OVA-expressing cells instead of OVA-secreting cells in parts of the text and cited reference Boissonnas et al. (2007. http://dx.doi.org/10.1084/jem.20061890) instead of Zeelenberg et al. (2008. http://dx.doi.org/10.1158/0008-5472.CAN-07-3163) and Sedlik et al. (2014. http://dx.doi.org/10.3402/jev.v3.24646). The Results and discussion paragraph containing the corrected references and full bibliographic information appear below.Fil: Alloatti, Andrés. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Rosario. Instituto de Biología Molecular y Celular de Rosario. Universidad Nacional de Rosario. Facultad de Ciencias Bioquímicas y Farmacéuticas. Instituto de Biología Molecular y Celular de Rosario; ArgentinaFil: Rookhuizen, Derek C.. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Joannas, Leonel. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Carpier, Jean-Marie. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Iborra, Salvador. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Magalhaes, Joao G.. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Yatim, Nader. Institut Pasteur, Paris; FranciaFil: Kozik, Patrycja. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Sancho, David. Institute Curie. U-932 Immunity And Cancer; FranciaFil: Albert, Matthew L.. Institut Pasteur, Paris; FranciaFil: Amigorena, Sebastian. Institute Curie. U-932 Immunity And Cancer; Franci

Small Molecule Enhancers of Endosome-to-Cytosol Import Augment Anti-tumor Immunity

International audienceCross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers

Rab6-dependent retrograde traffic of LAT controls immune synapse formation and T cell activation

International audienceThe adapter molecule linker for activation of T cells (LAT) orchestrates the formation of signalosomes upon T cell receptor (TCR) stimulation. LAT is present in different intracellular pools and is dynamically recruited to the immune synapse upon stimulation. However, the intracellular traffic of LAT and its function in T lymphocyte activation are ill defined. We show herein that LAT, once internalized, transits through the Golgi-trans-Golgi network (TGN), where it is repolarized to the immune synapse. This retrograde transport of LAT depends on the small GTPase Rab6 and the target soluble N-ethylmaleimide-sensitive factor attachment protein receptor (t-SNARE) Syntaxin-16, two regulators of the endosome-to-Golgi/TGN retrograde transport. We also show in vitro in Syntaxin-16- or Rab6-silenced human cells and in vivo in CD4+ T lymphocytes of the Rab6 knockout mouse that this retrograde traffic controls TCR stimulation. These results establish that the retrograde traffic of LAT from the plasma membrane to the Golgi-TGN controls the polarized delivery of LAT at the immune synapse and T lymphocyte activation

Gas6/Axl pathway is activated in chronic liver disease and its targeting reduces fibrosis via hepatic stellate cell inactivation

Background & AimsLiver fibrosis, an important health concern associated to chronic liver injury that provides a permissive environment for cancer development, is characterized by accumulation of extracellular matrix components mainly derived from activated hepatic stellate cells (HSCs). Axl, a receptor tyrosine kinase and its ligand Gas6, are involved in cell differentiation, immune response and carcinogenesis.MethodsHSCs were obtained from WT and Axl−/− mice, treated with recombinant Gas6 protein (rGas6), Axl siRNAs or the Axl inhibitor BGB324, and analyzed by western blot and real-time PCR. Experimental fibrosis was studied in CCl4-treated WT and Axl−/− mice, and in combination with Axl inhibitor. Gas6 and Axl serum levels were measured in alcoholic liver disease (ALD) and hepatitis C virus (HCV) patients.ResultsIn primary mouse HSCs, Gas6 and Axl levels paralleled HSC activation. rGas6 phosphorylated Axl and AKT prior to HSC phenotypic changes, while Axl siRNA silencing reduced HSC activation. Moreover, BGB324 blocked Axl/AKT phosphorylation and diminished HSC activation. In addition, Axl−/− mice displayed decreased HSC activation in vitro and liver fibrogenesis after chronic damage by CCl4 administration. Similarly, BGB324 reduced collagen deposition and CCl4-induced liver fibrosis in mice. Importantly, Gas6 and Axl serum levels increased in ALD and HCV patients, inversely correlating with liver functionality.ConclusionsThe Gas6/Axl axis is required for full HSC activation. Gas6 and Axl serum levels increase in parallel to chronic liver disease progression. Axl targeting may be a therapeutic strategy for liver fibrosis management

Toll-like receptor 4 engagement on dendritic cells restrains phago-lysosome fusion and promotes cross-presentation of antigens

The initiation of cytotoxic immune responses by dendritic cells (DCs) requires the presentation of antigenic peptides derived from phagocytosed microbes and infected or dead cells to CD8(+) T cells, a process called cross-presentation. Antigen cross-presentation by non-activated DCs, however, is not sufficient for the effective induction of immune responses. Additionally, DCs need to be activated through innate receptors, like Toll-like receptors (TLRs). During DC maturation, cross-presentation efficiency is first upregulated and then turned off. Here we show that during this transient phase of enhanced cross-presentation, phago-lysosome fusion was blocked by the topological re-organization of lysosomes into perinuclear clusters. LPS-induced lysosomal clustering, inhibition of phago-lysosome fusion and enhanced cross-presentation, all required expression of the GTPase Rab34. We conclude that TLR4 engagement induces a Rab34-dependent re-organization of lysosomal distribution that delays antigen degradation to transiently enhance cross- presentation, thereby optimizing the priming of CD8(+) T cell responses against pathogens

T Cell-Derived Protein S Engages TAM Receptor Signaling in Dendritic Cells to Control the Magnitude of the Immune Response

Dendritic cell (DC) activation is essential for the induction of immune defense against pathogens, yet needs to be tightly controlled to avoid chronic inflammation and exaggerated immune responses. Here, we identify a mechanism of immune homeostasis by which adaptive immunity, once triggered, tempers DC activation and prevents overreactive immune responses. T cells, once activated, produced Protein S (Pros1) that signaled through TAM receptor tyrosine kinases in DCs to limit the magnitude of DC activation. Genetic ablation of Pros1 in mouse T cells led to increased expression of costimulatory molecules and cytokines in DCs and enhanced immune responses to T cell-dependent antigens, as well as increased colitis. Additionally, PROS1 was expressed in activated human T cells, and its ability to regulate DC activation was conserved. Our results identify a heretofore unrecognized, homeostatic negative feedback mechanism at the interface of adaptive and innate immunity that maintains the physiological magnitude of the immune response.Fil: Carrera Silva, Eugenio Antonio. University of Yale. School of Medicine; Estados Unidos de América; Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental; Argentina;Fil: Chan, Pamela Y.. University of Yale. School of Medicine; Estados Unidos de América;Fil: Joannas, Leonel. University of Yale. School of Medicine; Estados Unidos de América;Fil: Errasti, Andrea Emilse. Universidad de Buenos Aires. Facultad de Medicina. Cátedra de Farmacología; Argentina; University of Yale. School of Medicine; Estados Unidos de América; Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina;Fil: Gagliani, Nicola. University of Yale. School of Medicine; Estados Unidos de América;Fil: Bosurgi, Lidia. University of Yale. School of Medicine; Estados Unidos de América;Fil: Jabbour, Maurice. University Of Arizona; Estados Unidos de América;Fil: Perry, Anthony. Banner MD Anderson Cancer Center; Estados Unidos de América;Fil: Smith Chakmakova, Faye. Saint Joseph’s Hospital and Medical Center; Estados Unidos de América;Fil: Mucida, Daniel. La Jolla Institute for Allergy and Immunology; Estados Unidos de América;Fil: Cheroutre, Hilde. La Jolla Institute for Allergy and Immunology; Estados Unidos de América;Fil: Burstyn Cohen, Tal. Salk Institute for Biological Studies; Estados Unidos de América;Fil: Leighton, Jonathan A.. Mayo Clinic Arizona; Estados Unidos de América;Fil: Lemke, Greg. Salk Institute for Biological Studies; Estados Unidos de América;Fil: Ghosh, Sourav. University Of Arizona; Estados Unidos de América;Fil: Rothlin, Carla V.. University of Yale. School of Medicine; Estados Unidos de América

The long noncoding RNA Morrbid regulates CD8 T cells in response to viral infection.

The transcriptional programs that regulate CD8 T-cell differentiation and function in the context of viral infections or tumor immune surveillance have been extensively studied; yet how long noncoding RNAs (lncRNAs) and the loci that transcribe them contribute to the regulation of CD8 T cells during viral infections remains largely unexplored. Here, we report that transcription of the lncRNA Morrbid is specifically induced by T-cell receptor (TCR) and type I IFN stimulation during the early stages of acute and chronic lymphocytic choriomeningitis virus (LCMV) infection. In response to type I IFN, the Morrbid RNA and its locus control CD8 T cell expansion, survival, and effector function by regulating the expression of the proapoptotic factor, Bcl2l11, and by modulating the strength of the PI3K-AKT signaling pathway. Thus, our results demonstrate that inflammatory cue-responsive lncRNA loci represent fundamental mechanisms by which CD8 T cells are regulated in response to pathogens and potentially cancer

The gut microbiota regulates white adipose tissue inflammation and obesity via a family of microRNAs.

The gut microbiota is a key environmental determinant of mammalian metabolism. Regulation of white adipose tissue (WAT) by the gut microbiota is a process critical to maintaining metabolic fitness, and gut dysbiosis can contribute to the development of obesity and insulin resistance (IR). However, how the gut microbiota regulates WAT function remains largely unknown. Here, we show that tryptophan-derived metabolites produced by the gut microbiota controlled the expression of the miR-181 family in white adipocytes in mice to regulate energy expenditure and insulin sensitivity. Moreover, dysregulation of the gut microbiota-miR-181 axis was required for the development of obesity, IR, and WAT inflammation in mice. Our results indicate that regulation of miR-181 in WAT by gut microbiota-derived metabolites is a central mechanism by which host metabolism is tuned in response to dietary and environmental changes. As we also found that MIR-181 expression in WAT and the plasma abundance of tryptophan-derived metabolites were dysregulated in a cohort of obese human children, the MIR-181 family may represent a potential therapeutic target to modulate WAT function in the context of obesity

The TAM family receptor tyrosine kinase TYRO3 is a negative regulator of type 2 immunity

Host responses against metazoan parasites or an array of environmental substances elicit type 2 immunity. Despite its protective function, type 2 immunity also drives allergic diseases. The mechanisms that regulate the magnitude of the type 2 response remain largely unknown. Here, we show that genetic ablation of a receptor tyrosine kinase encoded byTyro3in mice or the functional neutralization of its ortholog in human dendritic cells resulted in enhanced type 2 immunity. Furthermore, the TYRO3 agonist PROS1 was induced in T cells by the quintessential type 2 cytokine, interleukin-4. T cell-specificPros1knockouts phenocopied the loss ofTyro3 Thus, a PROS1-mediated feedback from adaptive immunity engages a rheostat, TYRO3, on innate immune cells to limit the intensity of type 2 responses.Fil: Chan, Pamela Y.. University of Yale. School of Medicine; Estados UnidosFil: Carrera Silva, Eugenio Antonio. University of Yale. School of Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: De Kouchkovsky, Dimitri. University of Yale. School of Medicine; Estados UnidosFil: Joannas, Leonel D.. University of Yale. School of Medicine; Estados UnidosFil: Hao, Liming. University of Yale. School of Medicine; Estados UnidosFil: Hu, Donglei. University of California; Estados UnidosFil: Huntsman, Scott. University of California; Estados UnidosFil: Eng, Celeste. University of California; Estados UnidosFil: Licona Limón, Paula. University of Yale. School of Medicine; Estados UnidosFil: Weinstein, Jason S.. University of Yale. School of Medicine; Estados UnidosFil: De Broski, Herbert R.. University of California; Estados UnidosFil: Craft , Joseph E.. University of Yale. School of Medicine; Estados UnidosFil: Flavell, Richard A.. University of Yale. School of Medicine; Estados UnidosFil: Repetto, Silvia. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Houssay. Instituto de Investigaciones en Microbiología y Parasitología Médica. Universidad de Buenos Aires. Facultad de Medicina. Instituto de Investigaciones en Microbiología y Parasitología Médica; Argentina. Universidad de Buenos Aires. Facultad de Medicina. Hospital de Clínicas General San Martín; ArgentinaFil: Correale, Jorge. Fundación para la Lucha Contra las Enfermedades Neurológicas de la Infancia. Instituto de Investigaciones Neurológicas ; ArgentinaFil: Burchard, Esteban G.. University of California; Estados UnidosFil: Torgerson, Dora G.. University of California; Estados UnidosFil: Ghosh, Sourav. University of Yale. School of Medicine; Estados UnidosFil: Rothlin, Carla V.. University of Yale. School of Medicine; Estados Unido