Función de las células dendriticas de tipo I en la identificación de subconjuntos de linfocitos T CD8 en respuesta a la infección por el virus VRS

El virus respiratorio sincitial (VRS) es conocido como una de las principales causas de enfermedad respiratoria en bebés, siendo casi todos los niños de dos años infectados al menos una vez por el VRS.Las células dendríticas (DCs) son células presentadoras de antígenos (APCs) que se encuentran en los tejidos periféricos y linfáticos y sirven como centinelas de las agresiones inmunológicas. Por ello, las DCs sirven de intermediarias entre la inmunidad innata y la adaptativa.Durante este proyecto nos propusimos estudiar el efecto de la falta de células dendríticas convencionales tipo I (cDC1) en dos subconjuntos diferentes de células T CD8+ epítopo- específicas tras la infección y la reinfección por el VRS. De este modo, intentamos identificar el papel de cDC1 en la activación de estos subconjuntos. Para ello, utilizamos ratones XCR1.cre y ratones de tipo salvaje en tres condiciones diferentes: control (inyectados en ambos momentos con solución Mock), primera infección (inyectados con Mock y VRS) y reinfección (inyectados en ambos momentos con VRS).Además, queríamos estudiar el efecto de la ausencia de cDC1 sobre la patología y la memoria inmune, ya que ambas están relacionadas con la función de las células T CD8+. Para ello controlamos el peso y realizamos una q-PCR.Los resultados de este proyecto mostraron la importancia de la presentación cruzada de cDC1 en la activación de las células T CD4 y CD8. Además, el estudio de dos poblaciones CD8+ CD69+ con diferentes TCR sugiere una dependencia diferente en cDC para la activación en función del tipo de antígeno. Todo esto podría servir de guía para el desarrollo de vacunas e inmunoterapias contra el VRS.<br /

Generation and transcriptional programming of intestinal dendritic cells: essential role of retinoic acid

The vitamin A metabolite retinoic acid (RA) regulates adaptive immunity in the intestines, with well-characterized effects on IgA responses, Treg induction and gut trafficking of T and B effector cells. It also controls the generation of cDC precursors in the bone marrow and regulates cDC subset representation, but its roles in the specialization of intestinal cDC subsets is understudied. Here we show that RA acts cell-intrinsically in developing gut-tropic pre-mucosal DC (pre-μDC) to effect the differentiation and drive the specialization of intestinal CD103+CD11b− (cDC1) and of CD103+CD11b+ (cDC2). Systemic deficiency or DC-restricted antagonism of RA signaling resulted in altered phenotypes of intestinal cDC1 and cDC2, and reduced numbers of cDC2. Effects of dietary deficiency were most apparent in the proximal small intestine, and were rapidly reversed by reintroducing vitamin A. In cultures of pre-μDC with Flt3L and GM-CSF, RA induced cDC with characteristic phenotypes of intestinal cDC1 and cDC2 by controlling subset-defining cell surface receptors, regulating subset-specific transcriptional programs, and suppressing proinflammatory NF-κB-dependent gene expression. Thus RA is required for transcriptional programming and maturation of intestinal cDC, and with GM-CSF and Flt3L provides a minimal environment for in vitro generation of intestinal cDC1- and cDC2-like cDC from specialized precursors

Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease

The scurfy mutant mouse strain suffers from a fatal lymphoproliferative disease leading to early death within 3–4 wk of age. A frame-shift mutation of the forkhead box transcription factor Foxp3 has been identified as the molecular cause of this multiorgan autoimmune disease. Foxp3 is a central control element in the development and function of regulatory T cells (T reg cells), which are necessary for the maintenance of self-tolerance. However, it is unclear whether dysfunction or a lack of T reg cells is etiologically involved in scurfy pathogenesis and its human correlate, the IPEX syndrome. We describe the generation of bacterial artificial chromosome–transgenic mice termed “depletion of regulatory T cell” (DEREG) mice expressing a diphtheria toxin (DT) receptor–enhanced green fluorescent protein fusion protein under the control of the foxp3 gene locus, allowing selective and efficient depletion of Foxp3+ T reg cells by DT injection. Ablation of Foxp3+ T reg cells in newborn DEREG mice led to the development of scurfy-like symptoms with splenomegaly, lymphadenopathy, insulitis, and severe skin inflammation. Thus, these data provide experimental evidence that the absence of Foxp3+ T reg cells is indeed sufficient to induce a scurfy-like phenotype. Furthermore, DEREG mice will allow a more precise definition of the function of Foxp3+ T reg cells in immune reactions in vivo

Ácidos grasos como marcadores de las relaciones tróficas entre el sestón, el zooplancton crustáceo y el sifonóforo Nanomia cara en Georges Basin y el cañón Oceanographer (NO Atlántico)

[EN] Fatty acid concentrations expressed as percentages of total fatty acid pools in seston, stage V copepodites of Calanus finmarchicus, adults of the euphausiid Meganyctiphanes norvegica, and the physonect siphonophore Nanomia cara were used to elucidate trophic links in Georges Basin and Oceanographer Canyon in September 2003. Seston at both locations was refractory and comprised mainly of saturated fatty acids. Phytoplankton did not contribute significantly to the fatty acid composition of seston or higher trophic levels. Only four fatty acids, i.e. 14:0, 16:0, 16:1 (n–7) and 18:1 (n–7), were transferred from seston to C. finmarchicus or M. norvegica, which suggested weak trophic interactions. Fatty acids transferred from the two species of crustaceans to N. cara included the same four fatty acids, along with three polyunsaturated fatty acids found in relatively high concentrations in both crustaceans, i.e. 20:3 (n–6), 20:5 (n–3) and 22:6 (n–3). In addition, 18:1 (n–9), which occurred in relatively high concentrations only in M. norvegica, and 18:0 and 18:2 (n–6), which were found in low concentrations in both crustaceans, also appeared to be transferred to N. cara. Overall, fatty acid trophic markers proved useful for identifying trophic links to N. cara[ES] En este estudio se utilizaron las concentraciones de ácidos grasos (expresadas como porcentajes) para identificar posibles relaciones tróficas entre el seston, el estadio V (copepoditos) de Calanus finmarchicus, los adultos del eufáusido Meganyctiphanes norvegica, y el sifonóforo fisonecto Nanomia cara en Georges Basin y el cañón submarino Oceanographer durante Septiembre de 2003. En ambos lugares el seston era muy refractario y compuesto básicamente por ácidos grasos saturados. El fitoplancton no contribuyó de forma significativa a la composición de ácidos grasos del seston o de niveles tróficos superiores. Sólo cuatro ácidos grasos [14:0, 16:0, 16:1 (n–7) y 18:1 (n–7)] se transfirieron potencialmente del seston a C. finmarchicus o M. norvegica, lo que sugiere una débil conexión trófica entre estos eslabones de la cadena. Los ácidos grasos transferidos de las dos especies de zooplancton crustáceo a N. cara incluyen los mismos descritos más arriba y otros tres ácidos grasos poliinsaturados [20:3 (n–6), 20:5 (n–3) y 22:6 (n–3)] encontrados en concentraciones relativamente elevadas en ambos crustáceos. Además, tanto el 18:1 (n–9) (encontrado en elevadas concentraciones en M. norvegica) y los 18:0 y 18:2 (n–6) (encontrados en bajas concentraciones en ambas especies de crustáceos) se transfieren a N. cara. Los ácidos grasos demuestran ser una herramienta útil para identificar conexiones tróficas en N. caraA grant to MJY from the National Science Foundation (NSF-0002493), the European Project EUROGEL, and USDA CRIS Project FLA-FAS-03978 supported this workPeer reviewe

Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation

Regulatory T cells (T(reg) cells) are essential for self-tolerance and immune homeostasis. Lack of effector T cell (T(eff) cell) function and gain of suppressive activity by T(reg) cells are dependent on the transcriptional program induced by Foxp3. Here we report that repression of SATB1, a genome organizer that regulates chromatin structure and gene expression, was crucial for the phenotype and function of T(reg) cells. Foxp3, acting as a transcriptional repressor, directly suppressed the SATB1 locus and indirectly suppressed it through the induction of microRNAs that bound the SATB1 3' untranslated region. Release of SATB1 from the control of Foxp3 in T(reg) cells caused loss of suppressive function, establishment of transcriptional T(eff) cell programs and induction of T(eff) cell cytokines. Our data support the proposal that inhibition of SATB1-mediated modulation of global chromatin remodeling is pivotal for maintaining T(reg) cell functionality.Marc Beyer... Timothy Sadlon...Simon C Barry... et al

IL-23 to see:Gut DCs shine bright in inductive sites

The cytokine IL-23 plays important roles in intestinal barrier protection and integrity, but is also linked to chronic inflammation. In this issue of JEM, Ohara et al. (https://doi.org/10.1084/jem.20230923) provide clarity on the much-debated question of which cells produce IL-23.</p