Revisiting the prominent anti-tumoral potential of pre-mNK cells

Interferon-producing killer dendritic cells (IKDC) were first described for their outstanding anti-tumoral properties.The “IKDC” terminology implied the description of a novel DC subset and initiated a debate on their cellular lineage origin.This debate shifted the focus away from their notable anti-tumoral potential. IKDC were recently redefined as precursors to mature NK (mNK) cells and consequently renamed pre-mNK cells. Importantly, a putative human equivalent of pre-mNK cells was recently associated with improved disease outcome in cancer patients. It is thus timely to revisit the functional attributes as well as the therapeutic potential of pre-mNK cells in line with their newly defined NK-cell precursor function

Immunoregulatory CD4-CD8- T cells as a potential therapeutic tool for transplantation, autoimmunity, and cancer

A central objective in organ transplantation and the treatment or prevention of autoimmune disease is the achievement of antigen-specific immune tolerance. An additional challenge in bone marrow transplantation for the treatment of hematological malignancies is the prevention of graft-vs-host disease (GVHD) while maintaining graft-vs-tumor activity. Interestingly, CD4-CD8- (double negative, DN) T cells, which exhibit a unique antigen-specific immunoregulatory potential, appear to exhibit all of the properties to respond to these challenges. Herein, we review the therapeutic potential of immunoregulatory DN T cells in various immunopathological settings, including graft tolerance, GVHD, cancer, and autoimmunity

Le point de vue des responsables des ressources de type familial sur les transformations des services de santé mentale au Québec

Cet article décrit les principaux résultats d’une étude qui a examiné le point de vue des responsables  de résidences d’accueil sur les récentes transformations des services en santé mentale, et sur l’impact de ces dernières sur leur travail auprès des personnes souffrant de troubles mentaux graves. Les résidences d’accueil (plus communément nommées « familles d’accueil ») représentent, au Québec, l’un des plus anciens modèles d’hébergement pouvant accueillir dans la communauté les personnes avec troubles mentaux graves. De fait, l’apparition des premières résidences d’accueil remonte au milieu des années 1950. Ainsi, bon nombre des individus qui ont dû quitter les unités de soins psychiatriques lorsque s’est amorcé au Québec le processus de désinstitutionnalisation, ont été placés dans des résidences d’accueil. Rappelons que les résidences d’accueil sont des habitations privées situées dans la communauté appartenant à des particuliers et dans lesquelles sont hébergées au plus, neuf personnes. Ces résidences d’accueil doivent offrir un environnement normal aux résidants, leurs responsables doivent veiller à la sécurité de ces derniers, en plus de leur procurer certains services matériels et d’encourager leur intégration sociale. Aujourd’hui les résidences d’accueil sont régies par la Loi 120 (Gouvernement du Québec, 1995) et sont désignées par l’appellation « ressources de type familial » (RTF).This article presents the major findings from a study that examined foster home caregivers’ views on the impact of the transformation of mental health services on caregivers and their work with persons with serious mental illness. In Québec foster homes, (or more commonly known as foster families), represent one of the oldest models of community based housing for persons with serious mental illness. In fact, the emergence of the first foster home dates back to the 1950ies. Over time, a large number of persons discharged from psychiatric hospitals during the process of deinstitutionalization were placed into these homes. Foster homes are private homes located in the community and operated by non professionals who can accommodate up to nine individuals. These residences provide a normal environment for its residents. Foster home caregivers must ensure a secure and safe environment as well as obtain certain services and encourage the social integration of the residents. Today foster homes are regulated by Bill 120 (Québec Government, 1995) and are designated as “family type resources” (RTF).Este artículo describe los principales resultados de un estudio que ha examinado el punto de vista de los responsables de las residencias de alojamiento acerca de las transformaciones recientes en los servicios de salud mental y el impacto de estos últimos en su trabajo con las personas que sufren de trastornos mentales graves. Las residencias de alojamiento (más comúnmente llamadas “familias de alojamiento”) representan en Quebec uno de los modelos de alojamiento más antiguos que pueden alojar en la comunidad a personas con trastornos mentales graves. De hecho, la aparición de las primeras residencias de alojamiento remontan a mediados de los años 1950. De este modo, un buen número de individuos que tuvieron que dejar las unidades de atención psiquiátrica cuando el proceso de desintitucionalización inició en Québec, fueron colocadas en las residencias de alojamiento. Recordemos que las residencias de alojamiento son habitaciones privadas situadas en la comunidad, que pertenecen a particulares y en las que se alojan como máximo nueve personas. Estas residencias deben ofrecer un ambiente normal a los residentes, sus responsables deben cuidar de la seguridad de los residentes, además de procurarles ciertos servicios materiales y alentar su integración social. Actualmente las residencias de alojamiento se rigen por la Ley 120 (Gobierno de Quebec, 1995) y son denominadas “recursos de tipo familiar” (RTF).Este artigo descreve os principais resultados de um estudo que examinou o ponto de vista dos responsáveis pelas residências sobre as recentes transformações dos serviços em saúde mental e sobre o impacto destas sobre seu trabalho junto às pessoas que sofrem de transtornos mentais graves. As residências (normalmente chamadas de “famílias de acolhimento”) representam, no Quebec, um dos mais antigos modelos de alojamento, podendo acolher na comunidade as pessoas com transtornos mentais graves. De fato, o aparecimento das primeiras residências data de meados dos anos 1950. Assim, várias pessoas, que tiveram que deixar as unidades de atendimento psiquiátricos, quando foi iniciado no Quebec o processo de desinstitucionalização, foram transferidas para as residências. Lembremos que as residências são domicílios privados, situados na comunidade, que pertencem a particulares, e nos quais são alojados no máximo nove pessoas. Estas residências devem oferecer um ambiente normal aos residentes, seus responsáveis devem garantir a segurança dos residentes, além de lhes fornecer alguns serviços materiais e encorajar sua integração social. Hoje, as residências são regidas pela Lei 120 (Governo do Quebec, 1995) e são designadas pelo nome de “recursos de tipo familiar” (RTF)

Restoring T cell homeostasis after allogeneic stem cell transplantation; principal limitations and future challenges

For several leukemia patients, allogeneic stem cell transplantation (allogeneic-SCT) is the unique therapeutic modality that could potentially cure their disease. Despite significant progress made in clinical management of allogeneic-SCT, acute graft-versushost disease (aGVHD) and infectious complications remain the second and third cause of death after disease recurrence. Clinical options to restore immunocompetence after allogeneic-SCT are very limited as studies have raised awareness about the safety with regards to graft-versus-host disease (GVHD). Preclinical works are now focusing on strategies to improve thymic functions and to restore the peripheral niche that have been damaged by alloreactive T cells. In this mini review, we will provide a brief overview about the adverse effects of GVHD on the thymus and the peripheral niche and the resulting negative outcome on peripheral T cell homeostasis. Finally, we will discuss the potential relevance of coordinating our studies on thymic rejuvenation and improvement of the peripheral lymphoid niche to achieve optimal T cell regeneration in GVHD patients

The potential causes of cystic fibrosis-related diabetes

Cystic fibrosis (CF) is a genetic disease caused by mutations in the cystic fibrosis transmembrane conductance regulator gene (CFTR). Cystic fibrosis-related diabetes (CFRD) is the most common comorbidity, affecting more than 50% of adult CF patients. Despite this high prevalence, the etiology of CFRD remains incompletely understood. Studies in young CF children show pancreatic islet disorganization, abnormal glucose tolerance, and delayed first-phase insulin secretion suggesting that islet dysfunction is an early feature of CF. Since insulin-producing pancreatic β-cells express very low levels of CFTR, CFRD likely results from β-cell extrinsic factors. In the vicinity of β-cells, CFTR is expressed in both the exocrine pancreas and the immune system. In the exocrine pancreas, CFTR mutations lead to the obstruction of the pancreatic ductal canal, inflammation, and immune cell infiltration, ultimately causing the destruction of the exocrine pancreas and remodeling of islets. Both inflammation and ductal cells have a direct effect on insulin secretion and could participate in CFRD development. CFTR mutations are also associated with inflammatory responses and excessive cytokine production by various immune cells, which infiltrate the pancreas and exert a negative impact on insulin secretion, causing dysregulation of glucose homeostasis in CF adults. In addition, the function of macrophages in shaping pancreatic islet development may be impaired by CFTR mutations, further contributing to the pancreatic islet structural defects as well as impaired first-phase insulin secretion observed in very young children. This review discusses the different factors that may contribute to CFRD

Identification of glycosylation sites essential for surface expression of the Caᵥα2δ1 subunit and modulation of the Cardiac Caᵥ1.2 channel activity

Alteration in the L-type current density is one aspect of the electrical remodeling observed in patients suffering from cardiac arrhythmias. Changes in channel function could result from variations in the protein biogenesis, stability, post-translational modification, and/or trafficking in any of the regulatory subunits forming cardiac L-type Ca2+ channel complexes. CaVα2δ1 is potentially the most heavily N-glycosylated subunit in the cardiac L-type CaV1.2 channel complex. Here, we show that enzymatic removal of N-glycans produced a 50-kDa shift in the mobility of cardiac and recombinant CaVα2δ1 proteins. This change was also observed upon simultaneous mutation of the 16 Asn sites. Nonetheless, the mutation of only 6/16 sites was sufficient to significantly 1) reduce the steady-state cell surface fluorescence of CaVα2δ1 as characterized by two-color flow cytometry assays and confocal imaging; 2) decrease protein stability estimated from cycloheximide chase assays; and 3) prevent the CaVα2δ1-mediated increase in the peak current density and voltage-dependent gating of CaV1.2. Reversing the N348Q and N812Q mutations in the non-operational sextuplet Asn mutant protein partially restored CaVα2δ1 function. Single mutation N663Q and double mutations N348Q/N468Q, N348Q/N812Q, and N468Q/N812Q decreased protein stability/synthesis and nearly abolished steady-state cell surface density of CaVα2δ1 as well as the CaVα2δ1-induced up-regulation of L-type currents. These results demonstrate that Asn-663 and to a lesser extent Asn-348, Asn-468, and Asn-812 contribute to protein stability/synthesis of CaVα2δ1, and furthermore that N-glycosylation of CaVα2δ1 is essential to produce functional L-type Ca2+ channels

Functional characterization of CaVα2δ mutations associated with sudden cardiac death

L-type Ca(2+) channels play a critical role in cardiac rhythmicity. These ion channels are oligomeric complexes formed by the pore-forming CaVα1 with the auxiliary CaVβ and CaVα2δ subunits. CaVα2δ increases the peak current density and improves the voltage-dependent activation gating of CaV1.2 channels without increasing the surface expression of the CaVα1 subunit. The functional impact of genetic variants of CACNA2D1 (the gene encoding for CaVα2δ), associated with shorter repolarization QT intervals (the time interval between the Q and the T waves on the cardiac electrocardiogram), was investigated after recombinant expression of the full complement of L-type CaV1.2 subunits in human embryonic kidney 293 cells. By performing side-by-side high resolution flow cytometry assays and whole-cell patch clamp recordings, we revealed that the surface density of the CaVα2δ wild-type protein correlates with the peak current density. Furthermore, the cell surface density of CaVα2δ mutants S755T, Q917H, and S956T was not significantly different from the cell surface density of the CaVα2δ wild-type protein expressed under the same conditions. In contrast, the cell surface expression of CaVα2δ D550Y, CaVα2δ S709N, and the double mutant D550Y/Q917H was reduced, respectively, by ≈30-33% for the single mutants and by 60% for the latter. The cell surface density of D550Y/Q917H was more significantly impaired than protein stability, suggesting that surface trafficking of CaVα2δ was disrupted by the double mutation. Co-expression with D550Y/Q917H significantly decreased CaV1.2 currents as compared with results obtained with CaVα2δ wild type. It is concluded that D550Y/Q917H reduced inward Ca(2+) currents through a defect in the cell surface trafficking of CaVα2δ. Altogether, our results provide novel insight in the molecular mechanism underlying the modulation of CaV1.2 currents by CaVα2δ

Failure to Censor Forbidden Clones of CD4 T Cells in Autoimmune Diabetes

Type 1 diabetes and other organ-specific autoimmune diseases often cluster together in human families and in congenic strains of NOD (nonobese diabetic) mice, but the inherited immunoregulatory defects responsible for these diseases are unknown. Here we track the fate of high avidity CD4 T cells recognizing a self-antigen expressed in pancreatic islet β cells using a transgenic mouse model. T cells of identical specificity, recognizing a dominant peptide from the same islet antigen and major histocompatibility complex (MHC)-presenting molecule, were followed on autoimmune susceptible and resistant genetic backgrounds. We show that non-MHC genes from the NOD strain cause a failure to delete these high avidity autoreactive T cells during their development in the thymus, with subsequent spontaneous breakdown of CD4 cell tolerance to the islet antigen, formation of intra-islet germinal centers, and high titre immunoglobulin G1 autoantibody production. In mixed bone marrow chimeric animals, defective thymic deletion was intrinsic to T cells carrying diabetes susceptibility genes. These results demonstrate a primary failure to censor forbidden clones of self-reactive T cells in inherited susceptibility to organ-specific autoimmune disease, and highlight the importance of thymic mechanisms of tolerance in organ-specific tolerance