Understanding the factors that impede immune responses to persistent viruses is essential in designing therapies for HIV infection. Mice infected with LCMV clone-13 have persistent high-level viremia ...and a dysfunctional immune response. Interleukin-7, a cytokine that is critical for immune development and homeostasis, was used here to promote immunity toward clone-13, enabling elucidation of the inhibitory pathways underlying impaired antiviral immune response. Mechanistically, IL-7 downregulated a critical repressor of cytokine signaling, Socs3, resulting in amplified cytokine production, increased T cell effector function and numbers, and viral clearance. IL-7 enhanced thymic output to expand the naive T cell pool, including T cells that were not LCMV specific. Additionally, IL-7 promoted production of cytoprotective IL-22 that abrogated liver pathology. The IL-7-mediated effects were dependent on endogenous IL-6. These attributes of IL-7 have profound implications for its use as a therapeutic in the treatment of chronic viral diseases.
Display omitted
► Socs3 is upregulated in T cells during chronic active viral infection in mice ► Deletion of socs3 in T cells prevents immune failure and promotes viral clearance ► In vivo IL-7 therapy represses Socs3 in T cells and clears chronic infection ► IL-7 promotes IL-22 production to mitigate immunopathology in chronic infection
We assessed the accuracy of the French version of the
Autism Spectrum Quotient
(
AQ
) in adolescents with Asperger syndrome (AS) and high-functioning autism (HFA) compared to healthy controls and ...adolescents with psychiatric disorders (PDs). Three groups of adolescents, aged 11–18, were assessed: 116 with AS/HFA (93 with IQ ≥ 85 and 20 with 70 ≤ IQ < 85), 39 with other PDs, and 199 healthy controls. The AS/HFA group scored significantly higher than the healthy control and PD groups. A cut-off score of 26 was used to differentiate the autism group from healthy controls with 0.89 sensitivity and 0.98 specificity. Scores did not vary by age or sex.
Autism spectrum disorder (ASD) is a common neurodevelopmental condition characterized by marked genetic heterogeneity. Recent studies of rare structural and sequence variants have identified hundreds ...of loci involved in ASD, but our knowledge of the overall genetic architecture and the underlying pathophysiological mechanisms remains incomplete. Glycine receptors (GlyRs) are ligand-gated chloride channels that mediate inhibitory neurotransmission in the adult nervous system but exert an excitatory action in immature neurons. GlyRs containing the α2 subunit are highly expressed in the embryonic brain, where they promote cortical interneuron migration and the generation of excitatory projection neurons. We previously identified a rare microdeletion of the X-linked gene GLRA2, encoding the GlyR α2 subunit, in a boy with autism. The microdeletion removes the terminal exons of the gene (GLRA2(Δex8-9)). Here, we sequenced 400 males with ASD and identified one de novo missense mutation, p.R153Q, absent from controls. In vitro functional analysis demonstrated that the GLRA2(Δex8)(-)(9) protein failed to localize to the cell membrane, while the R153Q mutation impaired surface expression and markedly reduced sensitivity to glycine. Very recently, an additional de novo missense mutation (p.N136S) was reported in a boy with ASD, and we show that this mutation also reduced cell-surface expression and glycine sensitivity. Targeted glra2 knockdown in zebrafish induced severe axon-branching defects, rescued by injection of wild type but not GLRA2(Δex8-9) or R153Q transcripts, providing further evidence for their loss-of-function effect. Glra2 knockout mice exhibited deficits in object recognition memory and impaired long-term potentiation in the prefrontal cortex. Taken together, these results implicate GLRA2 in non-syndromic ASD, unveil a novel role for GLRA2 in synaptic plasticity and learning and memory, and link altered glycinergic signaling to social and cognitive impairments.
This study examines change in 152 children over an almost 10-year period (T1: 4.9 (±1.3) years; T2: 8.1 (±1.3) years; T3: 15(±1.6) years) using a group-based, semi-parametric method in order to ...identify distinct developmental trajectories. Important deficits remain at adolescence in the adaptive abilities of children with Autism spectrum disorders, but changes in adaptive skills show two distinct growth rates. The univariate analysis reveals that low growth trajectories for both social and communication outcome are associated with the following characteristics at age 5: low cognitive and language skills, presence of epilepsy, and severity of autism. The multivariate analysis confirms that risk factors at age 5, were low language and severity of autism for both social and communication outcomes 10 years later, and that hours of early intervention was protective factor for communication.
Identifying key factors that enhance immune responses is crucial for manipulating immunity to tumors. We show that after a vaccine-induced immune response, adjuvant interleukin-7 (IL-7) improves ...antitumor responses and survival in an animal model. The improved immune response is associated with increased IL-6 production and augmented T helper type 17 cell differentiation. Furthermore, IL-7 modulates the expression of two ubiquitin ligases: Casitas B-lineage lymphoma b (Cbl-b), a negative regulator of T cell activation, is repressed, and SMAD-specific E3 ubiquitin protein ligase-2 (Smurf2) is enhanced, which antagonizes transforming growth factor-beta signaling. Notably, we show that although short term IL-7 therapy potently enhances vaccine-mediated immunity, in the absence of vaccination it is inefficient in promoting antitumor immune responses, despite inducing homeostatic proliferation of T cells. The ability of adjuvant IL-7 to antagonize inhibitory networks at the cellular and molecular level has major implications for immunotherapy in the treatment of tumors.
Register-based prevalence rates of childhood autism (CA), Asperger’s syndrome (AS) and other autism spectrum disorders (ASD) were calculated among children aged 7 years old of the 1997–2003 birth ...cohorts, living in four counties in France. The proportion of children presenting comorbidities was reported. 1123 children with ASD were recorded (M/F ratio: 4.1), representing an overall prevalence rate of 36.5/10,000 children (95 % CI 34.4–38.7): 8.8/10,000 for CA (95 % CI 7.8–9.9), 1.7/10,000 for AS (95 % CI 1.3–2.3) and 25.9/10,000 for other ASD (95 % CI 24.2–27.8). ASD prevalence significantly increased (
p
< 0.0001) during the period under study. The proportion of children with an intellectual disability was 47.3 %, all other comorbidities were present in less than 5 % of the cases.
This study evaluated whether atypical face processing in autism extends from human to cartoon faces for which they show a greater interest. Twenty children with autistic spectrum disorders (ASD) were ...compared to two groups of typically developing children, matched on chronological and mental age. They processed the emotional expressions of real faces, human cartoon and non-human cartoon faces. Children with ASD were as capable as controls in processing emotional expressions, but strategies differed according to the type of face. Controls relied on a configural strategy with all faces. By contrast, ASD children exploited this typical configural strategy with cartoons but used a local strategy with real faces. This atypical visual processing style is discussed in the context of face expertise.
Interleukin-7 (IL-7) is currently used in clinical trials to augment T-cell counts. Paradoxically, elevated systemic IL-7 found in lymphopenic humans is typically insufficient for CD4+ T-cell ...regeneration, and thymopoiesis becomes critical in this process. Here we show that the proliferative effect of IL-7 is more pronounced on CD4+CD8− thymocytes compared with peripheral CD4+ T cells. These cells express miR181a at higher levels and respond to lower concentrations of IL-7. As single-positive CD4+ thymocytes (CD4+SPT) exit the thymus, they rapidly diminish their proliferation to IL-7 therapy, and this is mediated, at least in part, by major histocompatibility complex class II distribution outside the thymus. Interestingly, increasing T-cell receptor (TCR) stimulation augments IL-7 responsiveness and proliferation of peripheral CD4+ T cells, whereas failure to stimulate TCR abrogates proliferation induced by IL-7. Finally, we demonstrated that IL-7 enhances the proliferation of CD4+ T cells that undergo “slow proliferation” in lymphopenic hosts. To date, our results indicate that TCR signaling is a major controlling factor for CD4 responsiveness and proliferation to IL-7 therapy.
•TCR stimulation increases IL-7 responsiveness.•CD4+SPT proliferate more to IL-7 therapy.
Interleukin-7 (IL-7), the principal cytokine implicated in thymopoiesis and peripheral T-cell homeostasis, is presently under evaluation in human diseases characterized by persistent lymphopenia. ...Unexpectedly, before the eventual IL-7–driven T-cell expansion, all treated patients showed a profound T-cell depletion 24 hours after injection. The current study uses the rhesus macaque model to investigate the mechanisms involved in this IL-7–induced T-cell depletion. We identify a new critical function of IL-7 that induces massive and rapid T-cell migration from the blood into various organs, including lymph nodes, parts of the intestine, and the skin. This homing process was initiated after the induction of chemokine receptor expression by circulating T cells and the production of corresponding chemokines in target organs. Finally, we demonstrate that the IL-7–induced cell cycling is initiated within these organs before T cells migrate back into the bloodstream, indicating that T-cell homing is required for in vivo IL-7 function.
PDF
