Expression Efficiency of Multiple Il9 Reporter Alleles Is Determined by Cell Lineage

Generation of allelic gene reporter mice has provided a powerful tool to study gene function in vivo. In conjunction with imaging technologies, reporter mouse models facilitate studies of cell lineage tracing, live cell imaging, and gene expression in the context of diseases. Although there are several advantages to using reporter mice, caution is important to ensure the fidelity of the reporter protein representing the gene of interest. In this study, we compared the efficiency of two Il9 reporter strains Il9citrine and Il9GFP in representing IL-9-producing CD4+ TH9 cells. Although both alleles show high specificity in IL-9-expressing populations, we observed that the Il9GFP allele visualized a much larger proportion of the IL-9-producing cells in culture than the Il9citrine reporter allele. In defining the mechanistic basis for these differences, chromatin immunoprecipitation and chromatin accessibility assay showed that the Il9citrine allele was transcriptionally less active in TH9 cells compared with the wild-type allele. The Il9citrine allele also only captured a fraction of IL-9-expressing bone marrow-derived mast cells. In contrast, the Il9 citrine reporter detected Il9 expression in type 2 innate lymphoid cells at a greater percentage than could be identified by IL-9 intracellular cytokine staining. Taken together, our findings demonstrate that the accuracy of IL-9 reporter mouse models may vary with the cell type being examined. These studies demonstrate the importance of choosing appropriate reporter mouse models that are optimal for detecting the cell type of interest as well as the accuracy of conclusions

The induction and function of the anti-inflammatory fate of TH17 cells

TH17 cells exemplify environmental immune adaptation: they can acquire both a pathogenic and an anti-inflammatory fate. However, it is not known whether the anti-inflammatory fate is merely a vestigial trait, or whether it serves to preserve the integrity of the host tissues. Here we show that the capacity of TH17 cells to acquire an anti-inflammatory fate is necessary to sustain immunological tolerance, yet it impairs immune protection against S. aureus. Additionally, we find that TGF-β signalling via Smad3/Smad4 is sufficient for the expression of the anti-inflammatory cytokine, IL-10, in TH17 cells. Our data thus indicate a key function of TH17 cell plasticity in maintaining immune homeostasis, and dissect the molecular mechanisms explaining the functional flexibility of TH17 cells with regard to environmental changes.Fil: Xu, Hao. University of Yale. School of Medicine; Estados UnidosFil: Agalioti, Theodora. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Zhao, Jun. University of Yale. School of Medicine; Estados UnidosFil: Steglich, Babett. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Wahib, Ramez. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Amezcua Vesely, Maria Carolina. University of Yale. School of Medicine; Estados Unidos. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Centro de Investigaciones en Bioquímica Clínica e Inmunología; ArgentinaFil: Bielecki, Piotr. University of Yale. School of Medicine; Estados UnidosFil: Bailis, Will. University of Yale. School of Medicine; Estados UnidosFil: Jackson, Ruaidhri. University of Yale. School of Medicine; Estados UnidosFil: Perez, Daniel. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Izbicki, Jakob. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Licona-Limón, Paula. University of Yale. School of Medicine; Estados UnidosFil: Kaartinen, Vesa. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Geginat, Jens. University Medical Center Hamburg-Eppendorf; AlemaniaFil: Esplugues, Enric. University of Yale. School of Medicine; Estados UnidosFil: Tolosa, Eva. University of Yale. School of Medicine; Estados UnidosFil: Huber, Samuel. University of Yale. School of Medicine; Estados UnidosFil: Flavell, Richard A.. University of Yale. School of Medicine; Estados UnidosFil: Gagliani, Nicola. University Medical Center Hamburg-Eppendorf; Alemani

Memoria inmunológica innata, la pieza faltante de la respuesta inmunológica

In the last decade, growing evidence has shed some light into an unrecognized capacity of the innate immune compartment: the unexpected ability of innate cells to enhance its response upon an immunological re-challenge. This capacity is called Trained immunity and resembles adaptive immune memory but lacks the specificity of antigen recognition by lymphocytes. Mechanistically, this type of memory or trained immunity, unlike somatic recombination or hypermutation of antigen-specific receptors in the adaptive memory; depends on pattern recognition receptors and metabolic changes that lead to long-term modifications on the epigenetic landscape, poising chromatin to readily express inflammatory cytokines upon a pathogenic re-challenge. In this review we will summarize and discuss the current progress made at elucidating the different innate cell populations with memory-like features, their receptors, downstream molecules and effector cytokines involved in the development and maintenance of trained immunity. This novel evidence overrides a very important dogma in immunology dissolving the boundaries separating innate and adaptive compartments of the immune system, and sets immunological memory as a shared mechanism of all immune cell types able to provide long-term protection to the host. Evidencia acumulada en la década pasada, ha demostrado una capacidad del compartimento inmune innato que había pasado desapercibida, esta es la habilidad inesperada de las células innatas de mejorar su respuesta frente a una reexposición inmunológica.  Esta capacidad se conoce como inmunidad entrenada y se parece a la memoria inmunológica adaptativa, sin embargo, carece de la especificidad de reconocimiento antigénico propio de los linfocitos. Mecanísticamente, este tipo de memoria o inmunidad entrenada, a diferencia de la recombinación somática e hipermutación de receptores antígeno-específicos en la memoria adaptativa; depende de receptores de reconocimiento de patrones y cambios metabólicos que llevan a modificaciones a largo plazo en el escenario epigenético, predisponiendo a la cromatina a expresar citocinas inflamatorias ante una re-exposición patogénica. En esta revisión resumiremos y discutiremos los avances científicos dilucidando las diferentes poblaciones innatas con propiedades de memoria, sus receptores, moléculas río abajo y citocinas efectoras involucradas en el desarrollo y mantenimiento de la memoria entrenada. Esta nueva evidencia rompe con un dogma muy importante en inmunología, eliminando las barreras que separan los compartimentos innatos y adaptativos del sistema immune, y posiciona a la memoria inmunológica como un mecanismo compartido por todos los tipos celulares inmunes capaz de proveer al hospedero de protección a largo plazo.

An IL-9-pulmonary macrophage axis defines the allergic lung inflammatory environment.

Despite IL-9 functioning as a pleiotropic cytokine in mucosal environments, the IL-9-responsive cell repertoire is still not well defined. Here, we found that IL-9 mediates proallergic activities in the lungs by targeting lung macrophages. IL-9 inhibits alveolar macrophage expansion and promotes recruitment of monocytes that develop into CD11c and CD11c interstitial macrophage populations. Interstitial macrophages were required for IL-9-dependent allergic responses. Mechanistically, IL-9 affected the function of lung macrophages by inducing Arg1 activity. Compared with Arg1-deficient lung macrophages, Arg1-expressing macrophages expressed greater amounts of CCL5. Adoptive transfer of Arg1 lung macrophages but not Arg1 lung macrophages promoted allergic inflammation that mice were protected against. In parallel, the elevated expression of IL-9, IL-9R, Arg1, and CCL5 was correlated with disease in patients with asthma. Thus, our study uncovers an IL-9/macrophage/Arg1 axis as a potential therapeutic target for allergic airway inflammation

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