IL-7 engages multiple mechanisms to overcome chronic viral infection and limit organ pathology.

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.

Meta-analysis of SHANK Mutations in Autism Spectrum Disorders: a gradient of severity in cognitive impairments.

SHANK genes code for scaffold proteins located at the post-synaptic density of glutamatergic synapses. In neurons, SHANK2 and SHANK3 have a positive effect on the induction and maturation of dendritic spines, whereas SHANK1 induces the enlargement of spine heads. Mutations in SHANK genes have been associated with autism spectrum disorders (ASD), but their prevalence and clinical relevance remain to be determined. Here, we performed a new screen and a meta-analysis of SHANK copy-number and coding-sequence variants in ASD. Copy-number variants were analyzed in 5,657 patients and 19,163 controls, coding-sequence variants were ascertained in 760 to 2,147 patients and 492 to 1,090 controls (depending on the gene), and, individuals carrying de novo or truncating SHANK mutations underwent an extensive clinical investigation. Copy-number variants and truncating mutations in SHANK genes were present in ∼1% of patients with ASD: mutations in SHANK1 were rare (0.04%) and present in males with normal IQ and autism; mutations in SHANK2 were present in 0.17% of patients with ASD and mild intellectual disability; mutations in SHANK3 were present in 0.69% of patients with ASD and up to 2.12% of the cases with moderate to profound intellectual disability. In summary, mutations of the SHANK genes were detected in the whole spectrum of autism with a gradient of severity in cognitive impairment. Given the rare frequency of SHANK1 and SHANK2 deleterious mutations, the clinical relevance of these genes remains to be ascertained. In contrast, the frequency and the penetrance of SHANK3 mutations in individuals with ASD and intellectual disability-more than 1 in 50-warrant its consideration for mutation screening in clinical practice.

TCR triggering modulates the responsiveness and homeostatic proliferation of CD4+ thymic emigrants to IL-7 therapy.

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.

[Autism spectrum disorders]. / Les troubles du spectre autistique.

Autism is an early onset neurodevelopmental syndrome, encompassing heterogeneous clinical situations and with disabling consequences for cognitive, social and emotional development. The condition is today considered to be a major public health issue.

Interleukin-7 treatment counteracts IFN-α therapy-induced lymphopenia and stimulates SIV-specific cytotoxic T lymphocyte responses in SIV-infected rhesus macaques.

Interferon-α (IFN-α)-based therapy is presently the standard treatment for hepatitis C virus (HCV)-infected patients. Despite good effectiveness, this cytokine is associated with major side effects, including significant lymphopenia, that limits its use for HIV/HCV-coinfected patients. Interleukin-7 (IL-7) has recently shown therapeutic potential and safety in several clinical trials designed to demonstrate T-cell restoration in immunodeficient patients. The purpose of this study was to evaluate, in simian immunodeficiency virus-infected rhesus macaques, the relevance of IL-7 therapy as a means to overcoming IFN-α-induced lymphopenia. We showed that low-dose IFN-α treatment induced strong lymphopenia in chronically infected monkeys. In contrast, high-dose IFN-α treatment stimulated IL-7 production, leading to increased circulating T-cell counts. Moreover, IL-7 therapy more than abrogated the lymphopenic effect of low-dose IFN-α. Indeed, the association of both cytokines resulted in increased circulating T-cell counts, in particular in the naive compartments, as a consequence of central and peripheral homeostatic functions of the IL-7. Finally, reduced PD-1 expression by memory CD8(+) T cells and transient T-cell repertoire diversification were observed under IL-7 therapy. Our data strongly suggest that IL-7 immunotherapy will be of substantial benefit in the treatment of HIV/HCV coinfection and should enhance the likelihood of HCV eradication in poorly responding patients.

Increased CD4+ T cell levels during IL-7 administration of antiretroviral therapy-treated simian immunodeficiency virus-positive macaques are not dependent on strong proliferative responses.

CD4(+) T cell depletion is a fundamental component of HIV infection and AIDS pathogenesis and is not always reversed following antiretroviral therapy (ART). In this study, the SIV-infected rhesus macaque model was used to assess recombinant simian IL-7 in its glycosylated form (rsIL-7gly) to enhance regeneration of CD4(+) T cells, particularly the crucial central memory compartment, after ART. We assessed the impact of rsIL-7gly administration as single injections and as a cluster of three doses. Irrespective of the dosing strategy used, the rsIL-7gly administration transiently increased proliferation of both central memory and naive cells, in both CD4(+) and CD8(+) subsets, without increasing SIV levels in the blood. Administration of rsIL-7gly at intervals of 4-6 wk maximized the proliferative response to therapy but resulted in only transient increases in peripheral blood T cell counts. Although more frequent rsIL-7gly "clustered" dosing (three times weekly with 2 wk of rest and then repeat) induced only an initial proliferative burst by CD4(+) T cells, this dosing strategy resulted in sustained increases in peripheral blood CD4(+) T cell counts. The clustered rsIL-7gly treatment regimen was shown to increase the half-life of a BrdU label among memory T cells in the blood when compared with that of macaques treated with ART alone, which is consistent with enhanced cell survival. These results indicate that dosing intervals have a major impact on the response to rsIL-7gly in SIV-positive ART-treated rhesus macaques and that optimum dosing strategies may be ones that induce CD4(+) T cell proliferation initially and provide increased CD4(+) T cell survival.

Injection of glycosylated recombinant simian IL-7 provokes rapid and massive T-cell homing in rhesus macaques.

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.

Typical emotion processing for cartoon but not for real faces in children with autistic spectrum disorders.

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 nonhuman 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.

Low but increasing prevalence of autism spectrum disorders in a French area from register-based data.

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.

The French version of the autism-spectrum quotient in adolescents: a cross-cultural validation study.

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.

Developmental trajectories of adaptive behaviors from early childhood to adolescence in a cohort of 152 children with autism spectrum disorders.

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.

A validated assay to measure soluble IL-7 receptor shows minimal impact of IL-7 treatment.

IL-7 is a crucial cytokine for T cell hematopoiesis and peripheral homeostasis which by signaling through its receptor alpha chain (CD127) is essential for inducing T cell proliferation and survival. Since the specific CD127 alpha chain is found in a soluble state (sCD127) and at a high level in plasma (ng/mL), it is important to develop a sensitive and reliable assay in order to investigate the potential role of this receptor in the regulation of IL-7 physiologic, physipathologic and therapeutic effects. We here report a fully validated method to measure sCD127 in human and simian plasma using a method based on ELISA MSD technology. We demonstrate that sCD127 is detectable at various levels in the plasma of healthy humans as well as in that of healthy Rhesus and Cynomolgus macaques (106.72, 205.26 and 366.95 ng/mL respectively). Moreover, as opposed to the sCD25/IL-2 tandem, we demonstrate that IL-7 treatment has no impact on sCD127 plasma concentration in patients infected by HIV.

Adjuvant IL-7 antagonizes multiple cellular and molecular inhibitory networks to enhance immunotherapies.

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.

Rapid modifications of peripheral T-cell subsets that express CD127 in macaques treated with recombinant IL-7.

BACKGROUND: Interleukin-7 (IL-7) is a key regulator of thymopoiesis and T-cell homeostasis, which increases blood T-cell number by enhancing thymic output of naive cells and peripheral proliferation. METHODS: We explored the effects of unglycosylated recombinant simian IL-7 (rsIL-7) administration on peripheral T-cell subpopulations in healthy macaques. RESULTS: RsIL-7 was well tolerated. Mean half-life ranged between 9.3 and 13.9 hours. Blood CD3(+)CD4(+) and CD3(+)CD8(+) lymphocyte counts decreased rapidly after each rsIL-7 administration, the duration of these effects being dependent on the frequency of administration. At treatment completion, the increased of CD3(+) lymphocytes was marked at 100 microg/kg every 2 days. CD3(+) lymphocytes that harbour the alpha chain of IL-7 receptor (CD127) and CD3(+)CD8(+) lymphocytes that expressed the proliferation marker Ki-67 exhibited a similar initial profile. The expression of the anti-apoptotic marker Bcl-2 increased in CD3(+) lymphocytes during the treatment and post-treatment period in a dose/frequency dependent manner. CONCLUSION: RsIL-7 was well tolerated in macaques and induces rapid modifications of T-cells that express CD127.

Recombinant interleukin-7 induces proliferation of naive macaque CD4+ and CD8+ T cells in vivo.

Interleukin-7 (IL-7) regulates T-cell homeostasis, and its availability is augmented in lymphopenic hosts. Naive CD8+ T cells transferred to lymphopenic mice acquire a memory-like phenotype, raising the possibility that IL-7 is the biological mediator of this effect. Here, we provide direct evidence that IL-7 induces the acquisition of memory-cell markers not only in CD8+ T cells but also in CD4+ T-cell subsets in immune-competent Indian rhesus macaques. The increase of these memory-like populations was dependent on the dose of the cytokine, and these cells were found in the blood as well as secondary lymphoid organs. Memory-like CD4+ and CD8+ T cells acquired the ability to secrete tumor necrosis factor alpha and, to a lesser extent, gamma interferon following stimulation with a cognate antigen. The phenotypic change observed in naive T cells was promptly reversed after discontinuation of IL-7. Importantly, IL-7 induced cycling of both CD4+ and CD8+ central memory and effector memory T cells, demonstrating its contribution to the maintenance of the entire T-cell pool. Thus, IL-7 may be of benefit in the treatment of iatrogenic or virus-induced T-cell depletion.