Coronin-1A Links Cytoskeleton Dynamics to TCRαβ-Induced Cell Signaling

Actin polymerization plays a critical role in activated T lymphocytes both in regulating T cell receptor (TCR)-induced immunological synapse (IS) formation and signaling. Using gene targeting, we demonstrate that the hematopoietic specific, actin- and Arp2/3 complex-binding protein coronin-1A contributes to both processes. Coronin-1A-deficient mice specifically showed alterations in terminal development and the survival of αβT cells, together with defects in cell activation and cytokine production following TCR triggering. The mutant T cells further displayed excessive accumulation yet reduced dynamics of F-actin and the WASP-Arp2/3 machinery at the IS, correlating with extended cell-cell contact. Cell signaling was also affected with the basal activation of the stress kinases sAPK/JNK1/2; and deficits in TCR-induced Ca2+ influx and phosphorylation and degradation of the inhibitor of NF-κB (IκB). Coronin-1A therefore links cytoskeleton plasticity with the functioning of discrete TCR signaling components. This function may be required to adjust TCR responses to selecting ligands accounting in part for the homeostasis defect that impacts αβT cells in coronin-1A deficient mice, with the exclusion of other lympho/hematopoietic lineages

Identification et caractérisation, grâce aux lignées de souris dérivées d'individus sauvages, d'une nouvelle population de lymphocytes B conservée dans le genre Mus (les cellules Bw)

L'utilisation de lignées de souris dérivées d individus sauvages nous a permis d identifier une nouvelle sous-population de lymphocytes B, nommée "Bw", qui se distingue par de nombreux critères des sous-populations de cellules B déjà connues chez la souris. Alors que la présence des cellules B-1a CD5pos est quasiment restreinte aux lignées de souris appartenant à la sous-espèce Mus musculus domesticus, les lymphocytes Bw sont conservés à travers l évolution du genre Mus. Les souris de laboratoire ont hérité la population B-1a CD5pos de la sous-espèce M.m. domesticus. Les lymphocytes Bw péritonéaux présentent le phénotype caractéristique suivant : CD19posCD5negMac-1posB220highIgMhighIgDhighCD43negCD9neg. Les cellules Bw sont retrouvées, à des fréquences variables dans la rate, les ganglions, la cavité péritonéale ainsi que les PBL. Le répertoire anticorps de ces lymphocytes est enrichi en spécificités autoréactives contre des antigènes tels que l ADN, la tubuline ou l actine, ainsi qu envers des globules rouges traités par de la broméline. En réponse au LPS et au CpG, ligands des TLR 4 et 9 respectivement, les cellules Bw produisent plus d anticorps anti-PC que les cellules B-2. Il en est de même suite à une immunisation par la bactérie S. pneumoniae. Les précurseurs issus de la moelle osseuse sont capables, au même titre que les précurseurs foetaux, de se différencier en cellules Bw, contrairement aux précurseurs des cellules B-1 qui sont enrichis dans le foie foetal. Ce travail révèle la présence d une nouvelle population de cellules B Mac-1pos, les lymphocytes Bw, conservée à travers l évolution du genre Mus et impliquée dans des réponses immunitaires innées.PARIS-BIUSJ-Physique recherche (751052113) / SudocSudocFranceF

Mecanismes cellulaires et moleculaires de la proliferation et de la differenciation des cellules #gamma##delta# murines au cours du developpement

SIGLEAvailable from INIST (FR), Document Supply Service, under shelf-number : AR 16482 / INIST-CNRS - Institut de l'Information Scientifique et TechniqueMinistere de l'Enseignement Superieur et de la Recherche, 75 - Paris (France)FRFranc

The Bw cells, a novel B cell population conserved in the whole genus Mus.

International audienceIn common laboratory mouse strains, which are derived from the crossing between three subspecies, peritoneal B cells are enriched in B-1a cells characterized by the CD5(+)Mac-1(+)B220(low)IgM(high)IgD(low)CD43(+)CD9(+) phenotype. Intriguingly in other vertebrates, CD5(+)Mac-1(+) cells have never been found in a specific anatomic site. To ascertain the peculiarity of the CD5(+) peritoneal B cells in laboratory mice, we analyzed the peritoneal B cell subsets in 9 inbred and 39 outbred wild-derived mouse strains belonging to 13 different species/subspecies. We found that most of these strains do not have the CD5(+) B-1a cell population. However, all of these strains including classical laboratory mouse strains, have variable proportions of a novel B cell population: Bw, which is characterized by a unique phenotype (CD5(-)Mac-1(+)B220(high)IgM(high)IgD(high)CD43(-)CD9(-)) and is not restricted to the peritoneal cavity. Bw cells are also distinct from both B-1 and B-2 cells from a functional point of view both by proliferative responses, cytokine secretion and Ab synthesis. Moreover, transfer experiments show that bone marrow and fetal liver cells from wild mice can give rise to Bw cells in alymphoid mice. The conservation of this B cell population, but not of the CD5(+) B-1a, during evolution of the genus Mus, its readiness to respond to TLR ligands and to produce high concentration of autoantibodies suggest that Bw cells play a key role in innate immunity

Wild-derived mouse strains, a valuable model to study B cell responses.

International audienceIn the present report, we revisited the B cell responsiveness of 7 wild-derived mouse strains to various toll-like receptor ligands (TLR-L). We found that 2 of them, namely PWK and STF presented profound defects in B cell proliferative responses to most of the TLR-L. Yet, their macrophage responses were largely unaffected, suggesting that regulation of TLR pathways are distinct in B cells and macrophages. We also showed that, anti-CD40 mAbs rescued the low proliferative responses to CpG in both PWK and STF B cells. In the other hand, CpG synergized with LPS to induce high levels of proliferation in STF B cells, which did not respond to LPS alone. Cytokine or immunoglobulin (Ig) productions, in vitro, were less impaired than the proliferative responses to LPS or CpG alone. In STF B cells, both ERK, P38 and JNK pathways were affected following in vitro TLR4 or TLR9 signaling. Moreover, while the basal levels of Ig secreting cells and of serum Igs were similar to that of control mice, antibody responses to both TI and TD antigens were severely affected, mainly in STF mice. Our findings therefore highlight the relevance of wild-derived mouse strains and TLR-L to study B cell physiology