Abatacept increases T cell exhaustion in early RA individuals who carry HLA risk alleles.

Exhausted CD8 T cells (TEX) are associated with worse outcome in cancer yet better outcome in autoimmunity. Building on our past findings of increased TIGIT+KLRG1+ TEX with teplizumab therapy in type 1 diabetes (T1D), in the absence of treatment we found that the frequency of TIGIT+KLRG1+ TEX is stable within an individual but differs across individuals in both T1D and healthy control (HC) cohorts. This TIGIT+KLRG1+ CD8 TEX population shares an exhaustion-associated EOMES gene signature in HC, T1D, rheumatoid arthritis (RA), and cancer subjects, expresses multiple inhibitory receptors, and is hyporesponsive in vitro, together suggesting co-expression of TIGIT and KLRG1 may broadly define human peripheral exhausted cells. In HC and RA subjects, lower levels of EOMES transcriptional modules and frequency of TIGIT+KLRG1+ TEX were associated with RA HLA risk alleles (DR0401, 0404, 0405, 0408, 1001) even when considering disease status and cytomegalovirus (CMV) seropositivity. Moreover, the frequency of TIGIT+KLRG1+ TEX was significantly increased in RA HLA risk but not non-risk subjects treated with abatacept (CTLA4Ig). The DR4 association and selective modulation with abatacept suggests that therapeutic modulation of TEX may be more effective in DR4 subjects and TEX may be indirectly influenced by cellular interactions that are blocked by abatacept.

Dysregulated IFN-γ signals promote autoimmunity in STAT1 gain-of-function syndrome.

Heterozygous signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations promote a clinical syndrome of immune dysregulation characterized by recurrent infections and predisposition to humoral autoimmunity. To gain insights into immune characteristics of STAT1-driven inflammation, we performed deep immunophenotyping of pediatric patients with STAT1 GOF syndrome and age-matched controls. Affected individuals exhibited dysregulated CD4+ T cell and B cell activation, including expansion of TH1-skewed CXCR3+ populations that correlated with serum autoantibody titers. To dissect underlying immune mechanisms, we generated Stat1 GOF transgenic mice (Stat1GOF mice) and confirmed the development of spontaneous humoral autoimmunity that recapitulated the human phenotype. Despite clinical resemblance to human regulatory T cell (Treg) deficiency, Stat1GOF mice and humans with STAT1 GOF syndrome exhibited normal Treg development and function. In contrast, STAT1 GOF autoimmunity was characterized by adaptive immune activation driven by dysregulated STAT1-dependent signals downstream of the type 1 and type 2 interferon (IFN) receptors. However, in contrast to the prevailing type 1 IFN-centric model for STAT1 GOF autoimmunity, Stat1GOF mice lacking the type 1 IFN receptor were only partially protected from STAT1-driven systemic inflammation, whereas loss of type 2 IFN (IFN-γ) signals abrogated autoimmunity. Last, germline STAT1 GOF alleles are thought to enhance transcriptional activity by increasing total STAT1 protein, but the underlying biochemical mechanisms have not been defined. We showed that IFN-γ receptor deletion normalized total STAT1 expression across immune lineages, highlighting IFN-γ as the critical driver of feedforward STAT1 elevation in STAT1 GOF syndrome.

The relevance of basic numerical skills for fraction processing: Evidence from cross-sectional data.

Recent research indicated that fraction understanding is an important predictor of later mathematical achievement. In the current study we investigated associations between basic numerical skills and students' fraction processing. We analyzed data of 939 German secondary school students (age range = 11.92 to 18.00 years) and evaluated the determinants of fraction processing considering basic numerical skills as predictors (i.e., number line estimation, basic arithmetic operations, non-symbolic magnitude comparison, etc.). Additionally, we controlled for general cognitive ability, grade level, and sex. We found that multiplication, subtraction, conceptual knowledge, number line estimation, and basic geometry were significantly associated with fraction processing beyond significant associations of general cognitive ability and sex. Moreover, relative weight analysis revealed that addition and approximate arithmetic should also be considered as relevant predictors for fraction processing. The current results provide food for thought that further research should focus on investigating whether recapitulating basic numerical content in secondary school mathematics education can be beneficial for acquiring more complex mathematical concepts such as fractions.

IL-6-targeted therapies to block the cytokine or its receptor drive distinct alterations in T cell function.

Therapeutics that inhibit IL-6 at different points in its signaling pathway are in clinical use, yet whether the immunological effects of these interventions differ based on their molecular target is unknown. We performed short-term interventions in individuals with type 1 diabetes using anti-IL-6 (siltuximab) or anti-IL-6 receptor (IL-6R; tocilizumab) therapies and investigated the impact of this in vivo blockade on T cell fate and function. Immune outcomes were influenced by the target of the therapeutic intervention (IL-6 versus IL-6R) and by peak drug concentration. Tocilizumab reduced ICOS expression on T follicular helper cell populations and T cell receptor-driven (TCR-driven) STAT3 phosphorylation. Siltuximab reversed resistance to Treg-mediated suppression and increased TCR-driven phosphorylated STAT3 and production of IL-10, IL-21, and IL-27 by T effectors. Together, these findings indicate that the context of IL-6 blockade in vivo drives distinct T cell-intrinsic changes that may influence therapeutic outcomes.

IL-6-Driven pSTAT1 Response Is Linked to T Cell Features Implicated in Early Immune Dysregulation.

Elevated levels and enhanced sensing of the pro-inflammatory cytokine interleukin-6 (IL-6) are key features of many autoimmune and inflammatory diseases. To better understand how IL-6 signaling may influence human T cell fate, we investigated the relationships between levels of components of the IL-6R complex, pSTAT responses, and transcriptomic and translational changes in CD4+ and CD8+ T cell subsets from healthy individuals after exposure to IL-6. Our findings highlight the striking heterogeneity in mbIL-6R and gp130 expression and IL-6-driven pSTAT1/3 responses across T cell subsets. Increased mbIL-6R expression correlated with enhanced signaling via pSTAT1 with less impact on pSTAT3, most strikingly in CD4+ naïve T cells. Additionally, IL-6 rapidly induced expression of transcription factors and surface receptors expressed by T follicular helper cells and altered expression of markers of apoptosis. Importantly, many of the features associated with the level of mbIL-6R expression on T cells were recapitulated both in the setting of tocilizumab therapy and when comparing donor CD4+ T cells harboring the genetic variant, IL6R Asp358Ala (rs2228145), known to alter mbIL-6R expression on T cells. Collectively, these findings should be taken into account as we consider the role of IL-6 in disease pathogenesis and translating IL-6 biology into effective therapies for T cell-mediated autoimmune disease.

Deep immune phenotyping reveals similarities between aging, Down syndrome, and autoimmunity.

Individuals with Down syndrome show cellular and clinical features of dysregulated aging of the immune system, including a shift from naïve to memory T cells and increased incidence of autoimmunity. However, a quantitative understanding of how various immune compartments change with age in Down syndrome remains lacking. Here, we performed deep immunophenotyping of a cohort of individuals with Down syndrome across the life span, selecting for autoimmunity-free individuals. We simultaneously interrogated age- and sex-matched healthy controls and people with type 1 diabetes as a representative autoimmune disease. We built an analytical software, IMPACD (Iterative Machine-assisted Permutational Analysis of Cytometry Data), that enabled us to rapidly identify many features of immune dysregulation in Down syndrome shared with other autoimmune diseases. We found quantitative and qualitative dysregulation of naïve CD4+ and CD8+ T cells in individuals with Down syndrome and identified interleukin-6 as a candidate driver of some of these changes, thus extending the consideration of immunopathologic cytokines in Down syndrome beyond interferons. We used immune cellular composition to generate three linear models of aging (immune clocks) trained on control participants. All three immune clocks demonstrated advanced immune aging in individuals with Down syndrome. One of these clocks, informed by Down syndrome­relevant biology, also showed advanced immune aging in individuals with type 1 diabetes. Orthologous RNA sequencing­derived immune clocks also demonstrated advanced immune aging in individuals with Down syndrome. Together, our findings demonstrate an approach to studying immune aging in Down syndrome that may have implications in other autoimmune diseases.

IL-6 receptor blockade does not slow ß cell loss in new-onset type 1 diabetes.

BackgroundIL-6 receptor (IL-6R) signaling drives development of T cell populations important to type 1 diabetes pathogenesis. We evaluated whether blockade of IL-6R with monoclonal antibody tocilizumab would slow loss of residual ß cell function in newly diagnosed type 1 diabetes patients.MethodsWe conducted a multicenter, randomized, placebo-controlled, double-blind trial with tocilizumab in new-onset type 1 diabetes. Participants were screened within 100 days of diagnosis. Eligible participants were randomized 2:1 to receive 7 monthly doses of tocilizumab or placebo. The primary outcome was the change from screening in the mean AUC of C-peptide collected during the first 2 hours of a mixed meal tolerance test at week 52 in pediatric participants (ages 6-17 years).ResultsThere was no statistical difference in the primary outcome between tocilizumab and placebo. Immunophenotyping showed reductions in downstream signaling of the IL-6R in T cells but no changes in CD4 memory subsets, Th17 cells, Tregs, or CD4+ T effector cell resistance to Treg suppression. A DC subset decreased during therapy but regressed to baseline once therapy stopped. Tocilizumab was well tolerated.ConclusionTocilizumab reduced T cell IL-6R signaling but did not modulate CD4+ T cell phenotypes or slow loss of residual ß cell function in newly diagnosed individuals with type 1 diabetes.Trial RegistrationClinicalTrials.gov NCT02293837.FundingNIH National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) and National Institute of Allergy and Infectious Diseases (NIAID) UM1AI109565, UL1TR000004 from NIH/National Center for Research Resources (NCRR) Clinical and Translational Science Award (CTSA), NIH/NIDDK P30DK036836, NIH/NIDDK U01DK103266, NIH/NIDDK U01DK103266, 1UL1TR000064 from NIH/NCRR CTSA, NIH/National Center for Advancing Translational Sciences (NCATS) UL1TR001878, UL1TR002537 from NIH/CTSA; National Health and Medical Research Council Practitioner Fellowship (APP1136735), NIH/NIDDK U01-DK085476, NIH/CTSA UL1-TR002494, Indiana Clinical and Translational Science Institute Award UL1TR002529, Vanderbilt Institute for Clinical and Translational Research UL1TR000445. NIH/NCATS UL1TR003142, NIH/CTSA program UL1-TR002494, Veteran Affairs Administration, and 1R01AI132774.

Preceding Viral Infections Do Not Imprint Long-Term Changes in Regulatory T Cell Function.

Regulatory T cells (Tregs) maintain peripheral self-tolerance and limit immune mediated pathology. Like effector T cells, Tregs can specialize in TH1-dominated immune responses and co-express T-bet together with Foxp3. This allows for expression of CXCR3 and efficient homing to sites of TH1 responses. However, whether such functional specialization is paralleled by memory generation among Tregs is unknown. In this study, we investigated the ability of polyclonal Tregs to form functional memory in response to viral infection. Using adoptive transfer models to compare infection-experienced Tregs generated upon acute Lymphocytic Choriomeningitis Virus (LCMV) WE and Vaccinia Virus (VV) infections with naive Tregs, we observed no differences in their phenotype or their in vivo maintenance. When comparing functional properties of infection-experienced and naive Tregs, we found no differences in in vitro suppressive capacity nor in their ability to limit the effector response upon homologous, systemic or local re-challenge in vivo. Our results suggest that no functional Treg memory is generated in the context of systemic LCMV or VV infection, but we cannot rule out the possibility that the generation of Treg memory may be possible in other contexts.

Time Reading in Middle and Secondary School Students: The Influence of Basic-Numerical Abilities.

Time reading skills are central for the management of personal and professional life. However, little is known about the differential influence of basic numerical abilities on analog and digital time reading in general and in middle and secondary school students in particular. The present study investigated the influence of basic numerical skills separately for analog and digital time reading in N = 709 students from 5th to 8th grade. The present findings suggest that the development of time reading skills is not completed by the end of primary school. Results indicated that aspects of magnitude manipulation and arithmetic fact knowledge predicted analog time reading significantly over and above the influence of age. Furthermore, results showed that spatial representations of number magnitude, magnitude manipulation, arithmetic fact knowledge, and conceptual knowledge were significant predictors of digital time reading beyond general cognitive ability and sex. To the best of our knowledge, the present study is the first to show differential effects of basic numerical abilities on analog and digital time reading skills in middle and secondary school students. As time readings skills are crucial for everyday life, these results are highly relevant to better understand basic numerical processes underlying time reading.

Rapid expansion of Treg cells protects from collateral colitis following a viral trigger.

Foxp3+ regulatory T (Treg) cells are essential for maintaining peripheral tolerance and preventing autoimmunity. While genetic factors may predispose for autoimmunity, additional environmental triggers, such as viral infections, are usually required to initiate the onset of disease. Here, we show that viral infection with LCMV results in type I IFN-dependent Treg cell loss that is rapidly compensated by the conversion and expansion of Vß5+ conventional T cells into iTreg cells. Using Vß5-deficient mice, we show that these Vß5+ iTreg cells are dispensable for limiting anti-viral immunity. Rather, the delayed replenishment of Treg cells in Vß5-deficient mice compromises suppression of microbiota-dependent activation of CD8+ T cells, resulting in colitis. Importantly, recovery from clinical symptoms in IBD patients is marked by expansion of the corresponding Vß2+ Treg population in humans. Collectively, we provide a link between a viral trigger and an impaired Treg cell compartment resulting in the initiation of immune pathology.

TIGIT limits immune pathology during viral infections.

Co-inhibitory pathways have a fundamental function in regulating T cell responses and control the balance between promoting efficient effector functions and restricting immune pathology. The TIGIT pathway has been implicated in promoting T cell dysfunction in chronic viral infection. Importantly, TIGIT signaling is functionally linked to IL-10 expression, which has an effect on both virus control and maintenance of tissue homeostasis. However, whether TIGIT has a function in viral persistence or limiting tissue pathology is unclear. Here we report that TIGIT modulation effectively alters the phenotype and cytokine profile of T cells during influenza and chronic LCMV infection, but does not affect virus control in vivo. Instead, TIGIT has an important effect in limiting immune pathology in peripheral organs by inducing IL-10. Our data therefore identify a function of TIGIT in limiting immune pathology that is independent of viral clearance.

Influences of basic numerical abilities on graph reading performance.

Understanding graphically presented information is an important aspect of modern mathematical and science literacy. In our study, we investigated the influence of basic numerical abilities on students' ability answer mathematical tasks with information presented in graphs. We analyzed data of 750 German students (grades 9-11) and evaluated the determinants of graph reading performance with multiple regression analysis using predictors of basic numerical abilities (such as number line estimation, basic arithmetic operations, etc.), considering also the influences of general cognitive ability, age, and gender. We found that number line estimation, subtraction, and conceptual knowledge were significant predictors of graph reading performance beyond the influences of general cognitive ability. This indicates that basic numerical abilities are still relevant for real-life problem solving in secondary school. We discuss possible mechanisms which directly (through respective arithmetic procedures) as well as indirectly (through mathematization of the problem) effectuate that basic numerical abilities graph reading performance.

Place-value computation in children with mathematics difficulties.

Recent research has provided initial evidence that children with math difficulties (MD) experience problems in processing place-value information in basic numerical tasks. However, it remains unclear whether these problems generalize to basic arithmetic operations. For instance, multi-digit addition problems with carryover specifically require the computation of place-value information. Yet little is known about the carry effect in children with MD. Therefore, the current study investigated whether problems in processing place-value information among third-grade children with MD (n = 29 9-year-olds) compared with an age-matched control group (n = 50) generalize to two-digit addition. The results indicate an increased carry effect for response latencies and error rates in children with MD. These findings suggest that deficits in processing place-value information among children with MD generalize to place-value computations in multi-digit arithmetic. Potential contributions of strategy use and working memory for difficulties in processing place-value information are discussed.

Conservation Abilities, Visuospatial Skills, and Numerosity Processing Speed: Association With Math Achievement and Math Difficulties in Elementary School Children.

The aim of the present study was to investigate the associations between elementary school children's mathematical achievement and their conservation abilities, visuospatial skills, and numerosity processing speed. We also assessed differences in these abilities between children with different types of learning problems. In Study 1 ( N = 229), we investigated second to fourth graders and in Study 2 ( N = 120), third and fourth graders. Analyses revealed significant contributions of numerosity processing speed and visuospatial skills to math achievement beyond IQ. Conservation abilities were predictive in Study 1 only. Children with math difficulties showed lower visuospatial skills and conservation abilities than children with typical achievement levels and children with reading and/or spelling difficulties, whereas children with combined difficulties explicitly showed low conservation abilities. These findings provide further evidence for the relations between children's math skills and their visuospatial skills, conservation abilities, and processing speed and contribute to the understanding of deficits that are specific to mathematical difficulties.

Basic numerical competences in large-scale assessment data: Structure and long-term relevance.

Basic numerical competences are seen as building blocks for later numerical and mathematical achievement. The current study aimed at investigating the structure of early numeracy reflected by different basic numerical competences in kindergarten and its predictive value for mathematical achievement 6 years later using data from large-scale assessment. This allowed analyses based on considerably large sample sizes (N > 1700). A confirmatory factor analysis indicated that a model differentiating five basic numerical competences at the end of kindergarten fitted the data better than a one-factor model of early numeracy representing a comprehensive number sense. In addition, these basic numerical competences were observed to reliably predict performance in a curricular mathematics test in Grade 6 even after controlling for influences of general cognitive ability. Thus, our results indicated a differentiated view on early numeracy considering basic numerical competences in kindergarten reflected in large-scale assessment data. Consideration of different basic numerical competences allows for evaluating their specific predictive value for later mathematical achievement but also mathematical learning difficulties.

Are WISC IQ scores in children with mathematical learning disabilities underestimated? The influence of a specialized intervention on test performance.

BACKGROUND: Intelligence measures play a pivotal role in the diagnosis of mathematical learning disabilities (MLD). Probably as a result of math-related material in IQ tests, children with MLD often display reduced IQ scores. However, it remains unclear whether the effects of math remediation extend to IQ scores. AIMS: The present study investigated the impact of a special remediation program compared to a control group receiving private tutoring (PT) on the WISC IQ scores of children with MLD. METHODS: We included N=45 MLD children (7-12 years) in a study with a pre- and post-test control group design. Children received remediation for two years on average. RESULTS: The analyses revealed significantly greater improvements in the experimental group on the Full-Scale IQ, and the Verbal Comprehension, Perceptual Reasoning, and Working Memory indices, but not Processing Speed, compared to the PT group. Children in the experimental group showed an average WISC IQ gain of more than ten points. CONCLUSION: Results indicate that the WISC IQ scores of MLD children might be underestimated and that an effective math intervention can improve WISC IQ test performance. Taking limitations into account, we discuss the use of IQ measures more generally for defining MLD in research and practice.

[Changes in psychological stress after interventions in children and adolescents with mathematical learning disabilities]. / Veränderungen psychischer Belastung durch die Förderung von rechenschwachen Kindern und Jugendlichen.

OBJECTIVE: The present study examined the effects of the Waterglass Intervention Program on children with mathematical learning disabilities compared to dyscalculic children who received private tutoring. METHOD: In a pre-post-control group design, N = 46 children (age 7-12) and their parents were questioned about changes in test anxiety, school reluctance, anxiety disorder, and internal and external abnormality. RESULTS: Children who attended the Waterglass Intervention Program reported a higher reduction of test anxiety, school reluctance, and attention problems. A trend toward a higher reduction of the CBCL-score was also found. These changes were mediated by the changes in math school grades. Furthermore, results showed that more children showed internal disorders than would be expected. CONCLUSIONS: An intervention specific for children with mathematical learning disabilities has positive effects on the psychological stress level of these children. Further research is required to investigate the mechanisms related to these changes and the effects on mathematical achievement.