Inactivation of cytidine triphosphate synthase 1 prevents fatal auto-immunity in mice.

De novo synthesis of the pyrimidine, cytidine triphosphate (CTP), is crucial for DNA/RNA metabolism and depends on the CTP synthetases, CTPS1 and -2. Partial CTPS1 deficiency in humans has previously been shown to lead to immunodeficiency, with impaired expansion of T and B cells. Here, we examine the effects of conditional and inducible inactivation of Ctps1 and/or Ctps2 on mouse embryonic development and immunity. We report that deletion of Ctps1, but not Ctps2, is embryonic-lethal. Tissue and cells with high proliferation and renewal rates, such as intestinal epithelium, erythroid and thymic lineages, activated B and T lymphocytes, and memory T cells strongly rely on CTPS1 for their maintenance and growth. However, both CTPS1 and CTPS2 are required for T cell proliferation following TCR stimulation. Deletion of Ctps1 in T cells or treatment with a CTPS1 inhibitor rescued Foxp3-deficient mice from fatal systemic autoimmunity and reduced the severity of experimental autoimmune encephalomyelitis. These findings support that CTPS1 may represent a target for immune suppression.

Role of IL-27 in Epstein-Barr virus infection revealed by IL-27RA deficiency.

Epstein-Barr virus (EBV) infection can engender severe B cell lymphoproliferative diseases1,2. The primary infection is often asymptomatic or causes infectious mononucleosis (IM), a self-limiting lymphoproliferative disorder3. Selective vulnerability to EBV has been reported in association with inherited mutations impairing T cell immunity to EBV4. Here we report biallelic loss-of-function variants in IL27RA that underlie an acute and severe primary EBV infection with a nevertheless favourable outcome requiring a minimal treatment. One mutant allele (rs201107107) was enriched in the Finnish population (minor allele frequency = 0.0068) and carried a high risk of severe infectious mononucleosis when homozygous. IL27RA encodes the IL-27 receptor alpha subunit5,6. In the absence of IL-27RA, phosphorylation of STAT1 and STAT3 by IL-27 is abolished in T cells. In in vitro studies, IL-27 exerts a synergistic effect on T-cell-receptor-dependent T cell proliferation7 that is deficient in cells from the patients, leading to impaired expansion of potent anti-EBV effector cytotoxic CD8+ T cells. IL-27 is produced by EBV-infected B lymphocytes and an IL-27RA-IL-27 autocrine loop is required for the maintenance of EBV-transformed B cells. This potentially explains the eventual favourable outcome of the EBV-induced viral disease in patients with IL-27RA deficiency. Furthermore, we identified neutralizing anti-IL-27 autoantibodies in most individuals who developed sporadic infectious mononucleosis and chronic EBV infection. These results demonstrate the critical role of IL-27RA-IL-27 in immunity to EBV, but also the hijacking of this defence by EBV to promote the expansion of infected transformed B cells.

DISSECT is a tool to segment and explore cell and tissue mechanics in highly deformed 3D epithelia.

Understanding morphogenesis strongly relies on the characterization of tissue topology and mechanical properties deduced from imaging data. The development of new imaging techniques offers the possibility to go beyond the analysis of mostly flat surfaces and image and analyze complex tissue organization in depth. An important bottleneck in this field is the need to analyze imaging datasets and extract quantifications not only of cell and tissue morphology but also of the cytoskeletal network's organization in an automatized way. Here, we describe a method, called DISSECT, for DisPerSE (Discrete Persistent Structure Extractor)-based Segmentation and Exploration of Cells and Tissues, that offers the opportunity to extract automatically, in strongly deformed epithelia, a precise characterization of the spatial organization of a given cytoskeletal network combined with morphological quantifications in highly remodeled three-dimensional (3D) epithelial tissues. We believe that this method, applied here to Drosophila tissues, will be of general interest in the expanding field of morphogenesis and tissue biomechanics.

Artificial Intelligence for Detecting Acute Fractures in Patients Admitted to an Emergency Department: Real-Life Performance of Three Commercial Algorithms.

RATIONALE AND OBJECTIVES: Interpreting radiographs in emergency settings is stressful and a burden for radiologists. The main objective was to assess the performance of three commercially available artificial intelligence (AI) algorithms for detecting acute peripheral fractures on radiographs in daily emergency practice. MATERIALS AND METHODS: Radiographs were collected from consecutive patients admitted for skeletal trauma at our emergency department over a period of 2 months. Three AI algorithms-SmartUrgence, Rayvolve, and BoneView-were used to analyze 13 body regions. Four musculoskeletal radiologists determined the ground truth from radiographs. The diagnostic performance of the three AI algorithms was calculated at the level of the radiography set. Accuracies, sensitivities, and specificities for each algorithm and two-by-two comparisons between algorithms were obtained. Analyses were performed for the whole population and for subgroups of interest (sex, age, body region). RESULTS: A total of 1210 patients were included (mean age 41.3 ± 18.5 years; 742 [61.3%] men), corresponding to 1500 radiography sets. The fracture prevalence among the radiography sets was 23.7% (356/1500). Accuracy was 90.1%, 71.0%, and 88.8% for SmartUrgence, Rayvolve, and BoneView, respectively; sensitivity 90.2%, 92.6%, and 91.3%, with specificity 92.5%, 70.4%, and 90.5%. Accuracy and specificity were significantly higher for SmartUrgence and BoneView than Rayvolve for the whole population (P < .0001) and for subgroups. The three algorithms did not differ in sensitivity (P = .27). For SmartUrgence, subgroups did not significantly differ in accuracy, specificity, or sensitivity. For Rayvolve, accuracy and specificity were significantly higher with age 27-36 than ≥53 years (P = .0029 and P = .0019). Specificity was higher for the subgroup knee than foot (P = .0149). For BoneView, accuracy was significantly higher for the subgroups knee than foot (P = .0006) and knee than wrist/hand (P = .0228). Specificity was significantly higher for the subgroups knee than foot (P = .0003) and ankle than foot (P = .0195). CONCLUSION: The performance of AI detection of acute peripheral fractures in daily radiological practice in an emergency department was good to high and was related to the AI algorithm, patient age, and body region examined.

Differential roles of CTP synthetases CTPS1 and CTPS2 in cell proliferation.

The CTP nucleotide is a key precursor of nucleic acids metabolism essential for DNA replication. De novo CTP production relies on CTP synthetases 1 and 2 (CTPS1 and CTPS2) that catalyze the conversion of UTP into CTP. CTP synthetase activity is high in proliferating cells including cancer cells; however, the respective roles of CTPS1 and CTPS2 in cell proliferation are not known. By inactivation of CTPS1 and/or CTPS2 and complementation experiments, we showed that both CTPS1 and CTPS2 are differentially required for cell proliferation. CTPS1 was more efficient in promoting proliferation than CTPS2, in association with a higher intrinsic enzymatic activity that was more resistant to inhibition by 3-deaza-uridine, an UTP analog. The contribution of CTPS2 to cell proliferation was modest when CTPS1 was expressed but essential in absence of CTPS1. Public databases analysis of more than 1,000 inactivated cancer cell lines for CTPS1 or CTPS2 confirmed that cell growth is highly dependent of CTPS1 but less or not of CTPS2. Therefore, our results demonstrate that CTPS1 is the main contributor to cell proliferation.

MAGT1 deficiency in XMEN disease is associated with severe platelet dysfunction and impaired platelet glycoprotein N-glycosylation.

BACKGROUND: X-linked immunodeficiency with magnesium defect, Epstein-Barr virus infection, and neoplasia (XMEN) disease is a primary immunodeficiency due to loss-of-function mutations in the gene encoding for magnesium transporter 1 (MAGT1). Furthermore, as MAGT1 is involved in the N-glycosylation process, XMEN disease is classified as a congenital disorder of glycosylation. Although XMEN-associated immunodeficiency is well described, the mechanisms underlying platelet dysfunction and those responsible for life-threatening bleeding events have never been investigated. OBJECTIVES: To assess platelet functions in patients with XMEN disease. METHODS: Two unrelated young boys, including one before and after hematopoietic stem cell transplantation, were investigated for their platelet functions, glycoprotein expression, and serum and platelet-derived N-glycans. RESULTS: Platelet analysis highlighted abnormal elongated cells and unusual barbell-shaped proplatelets. Platelet aggregation, integrin αIIbß3 activation, calcium mobilization, and protein kinase C activity were impaired between both patients. Strikingly, platelet responses to protease-activated receptor 1 activating peptide were absent at both low and high concentrations. These defects were also associated with decreased molecular weights of glycoprotein Ibα, glycoprotein VI, and integrin αIIb due to partial impairment of N-glycosylation. All these defects were corrected after hematopoietic stem cell transplantation. CONCLUSION: Our results highlight prominent platelet dysfunction related to MAGT1 deficiency and defective N-glycosylation in several platelet proteins that could explain the hemorrhages reported in patients with XMEN disease.

Saccharide isomerate ameliorates cosmetic scalp conditions in a Chinese study population.

BACKGROUND: Scalp conditions such as flaky or oily scalp affect people across ethnicities and age groups. In addition to flaking, increased sebum secretion, itching, and compromised scalp barrier function were described. Scalp conditions are aesthetically disturbing and may cause psychological distress in affected individuals who are looking for mild and effective treatment at the same time. Saccharide isomerate has a long history as a skin moisturizer, and it was found to improve skin barrier function, also suggesting possible beneficial effects on scalp. AIMS: To provide relevant claim substantiation to introduce saccharide isomerate as a new scalp care active against scalp flaking condition. MATERIAL AND METHODS: We conducted a placebo-controlled clinical study in an adult Chinese population affected by dandruff scalp as assessed by an adherent scalp flaking score. We monitored transepidermal water loss (TEWL), sebum secretion, and scalp flaking during 28 days. RESULTS: Formulations containing Saccharide isomerate significantly improved all parameters both over time as well as compared to the placebo formulation. CONCLUSION: We propose Saccharide isomerate for cosmetic formulations directed toward improving scalp conditions such as dandruff or oily scalp.

Inherited human ITK deficiency impairs IFN-γ immunity and underlies tuberculosis.

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αß T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αß and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αß T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in response to TCR crosslinking, mitogens, or forced synapse formation with autologous B lymphocytes. Finally, the patients' total lymphocytes secrete small amounts of IFN-γ, and CD4+, CD8+, DN αß T, Vδ2+ γδ T, and MAIT cells display impaired IFN-γ production in response to BCG. Inherited ITK deficiency undermines the development and function of various IFN-γ-producing T cell subsets, thereby underlying TB.

Human CARMIL2 deficiency underlies a broader immunological and clinical phenotype than CD28 deficiency.

Patients with inherited CARMIL2 or CD28 deficiency have defective T cell CD28 signaling, but their immunological and clinical phenotypes remain largely unknown. We show that only one of three CARMIL2 isoforms is produced and functional across leukocyte subsets. Tested mutant CARMIL2 alleles from 89 patients and 52 families impair canonical NF-κB but not AP-1 and NFAT activation in T cells stimulated via CD28. Like CD28-deficient patients, CARMIL2-deficient patients display recalcitrant warts and low blood counts of CD4+ and CD8+ memory T cells and CD4+ TREGs. Unlike CD28-deficient patients, they have low counts of NK cells and memory B cells, and their antibody responses are weak. CARMIL2 deficiency is fully penetrant by the age of 10 yr and is characterized by numerous infections, EBV+ smooth muscle tumors, and mucocutaneous inflammation, including inflammatory bowel disease. Patients with somatic reversions of a mutant allele in CD4+ T cells have milder phenotypes. Our study suggests that CARMIL2 governs immunological pathways beyond CD28.

mBeRFP: a versatile fluorescent tool to enhance multichannel live imaging and its applications.

Cell and developmental biology increasingly require live imaging of protein dynamics in cells, tissues or living organisms. Thanks to the discovery and development of a panel of fluorescent proteins over the last decades, live imaging has become a powerful and commonly used approach. However, multicolor live imaging remains challenging. The generation of long Stokes shift red fluorescent proteins offers interesting new perspectives to bypass this limitation. Here, we provide a detailed characterization of mBeRFP for in vivo live imaging and its applications in Drosophila. Briefly, we show that a single illumination source is sufficient to stimulate mBeRFP and GFP simultaneously. We demonstrate that mBeRFP can be easily combined with classical green and red fluorescent proteins without any crosstalk. We also show that the low photobleaching of mBeRFP is suitable for live imaging, and that this protein can be used for quantitative applications, such as FRAP or laser ablation. Finally, we believe that this fluorescent protein, with the set of new possibilities it offers, constitutes an important tool for cell, developmental and mechano-biologists in their current research.

An extract of Leontopodium alpinum inhibits catagen development ex vivo and increases hair density in vivo.

OBJECTIVES: Hair loss and reduction in hair volume are hallmarks of hair disorders, such as telogen effluvium, or male or female pattern hair loss, and hair ageing, which can cause severe distress in both men and women. Common anti-hair loss drugs carry some side effects; therefore, novel, safer approaches targeting milder phenotypes are highly advocated. In this context, we investigated an extract of the alpine plant Edelweiss, Leontopodium alpinum var. Helvetia, for its ability to modulate hair follicle (HF) growth ex vivo and inhibit hair loss while increasing hair regeneration in vivo. METHODS: Human amputated HFs were microdissected from three donors, two women and one man, and cultured ex vivo for 6 days. After treatment with 0.001% Edelweiss extract (EWDE), we investigated hair shaft production and anagen/catagen conversion, and measured known parameters associated with hair growth, that is hair matrix keratinocyte proliferation and apoptosis, dermal papilla inductivity, and growth factors, by quantitative (immuno)histomorphometry. To assess the anti-hair loss potential of the alpine plant compound, we performed a randomized, placebo-controlled human study enrolling Caucasian women and men, aged 18 to 65 years, with normal hair loss. After 5 months' daily use of an extract containing leave-on serum, we analysed hair density and anagen-to-catagen/telogen ratio by the Trichogram analysis. RESULTS: Our results revealed a significant prolongation in the anagen phase in HFs treated with 0.001% Edelweiss, as indicated by an increase in HFs remaining in anagen and a significant decrease in hair cycle score. In line with this effect, EWDE significantly stimulated hair matrix (HM) keratinocyte proliferation, and dermal papilla inductivity, as shown by a significant up-regulation of versican expression and alkaline phosphatase activity, and a tendential increase in FGF7 immunoreactivity in the dermal papilla of all HFs or only anagen VI HFs. Corroborating the ex vivo results, we observed a significant increase in growing hair shaft numbers (hair density) after treatment with Edelweiss extract formulation, and a tendential up-regulation in the anagen-to-catagen/telogen ratio. CONCLUSIONS: We show here, through several lines of evidence, that the selected extract of the alpine plant Leontopodium alpinum var Helvetia (Edelweiss) inhibits premature catagen induction, possibly by stimulating dermal papilla inductivity. It is therefore worth exploiting this extract clinically as an anti-hair loss agent, both for preventing ageing-associated hair shedding and as an adjuvant therapy for hair loss disorders.

OBJECTIFS: La perte de cheveux et la réduction du volume des cheveux sont caractéristiques des troubles capillaires, tels que l'effluvium télogène, ou la calvitie chez l'homme ou la femme, et le vieillissement des cheveux, qui peuvent causer une certaine détresse chez les hommes et les femmes. Les médicaments courants contre la chute des cheveux ont des effets secondaires, par conséquent, de nouvelles approches plus sûres ciblant des phénotypes légers sont fortement recommandées. Dans ce contexte, nous avons étudié un extrait de la plante alpine Edelweiss, Leontopodium alpinum var. Helvetia, pour sa capacité à stimuler la croissance du follicule pileux (HF) ex vivo et à inhiber la chute des cheveux tout en augmentant la régénération des fibres capillaires in vivo. MÉTHODES: Les follicules pileux (HF) humains prélevés ont été microdisséqués chez trois donneurs, deux femmes et un homme, et cultivés ex vivo pendant 6 jours. Après le traitement avec l'extrait d'Edelweiss à 0,001 % (EWDE), nous avons étudié la production de fibre capillaire et la conversion anagène/catagène, ainsi que mesuré les paramètres connus associés à la croissance des cheveux, à savoir, la prolifération des kératinocytes dans la matrice capillaire et l'apoptose, l'induction des papilles dermiques, et des facteurs de croissance, par (immuno-)histomorphométrie quantitative. Pour évaluer le potentiel des propriétés anti-chute du cheveu de l'extrait de plante alpine, nous avons réalisé une étude clinique aléatoire avec placebo, sur des femmes et des hommes de type caucasien âgés de 18 à 65 ans présentant une perte de cheveux normale. Après cinq mois d'utilisation quotidienne d'un sérum sans rinçage contenant l'extrait de plante, nous avons analysé la densité capillaire et le rapport anagène à catagène/télogène par trichogramme. RÉSULTATS: Nos résultats ont révélé une prolongation significative de la phase anagène dans les HF traités avec 0,001% d'Edelweiss, comme l'indique une augmentation des HF restant en phase anagène et une diminution significative du « hair cycle score ¼. En ligne avec cet effet, EWDE a stimulé de façon significative la matrice du cheveux (HM), la prolifération des kératinocytes, et l'induction de la papille dermique, comme le montre une augmentation significative de l'expression du versican et de l'activité de la phosphatase alcaline, et une augmentation tendancielle de l'immunoréactivité FGF7 dans la papille dermique de tous les HF ou seulement des HF anagènes VI. Corroborant les résultats ex vivo, nous avons observé une augmentation significative du nombre de fibres capillaires (densité de cheveux) après le traitement avec la formulation d'extrait d'Edelweiss, et une augmentation tendancielle dans le rapport anagène à catagène/télogène. CONCLUSIONS: Nous montrons ici, à travers plusieurs éléments de preuve, que l'extrait sélectionné de la plante alpine Leontopodium alpinum var Helvetia (Edelweiss) inhibe l'induction prématurée de la phase catagène, en stimulant la papille dermique. Il est donc possible d'utiliser cet extrait comme un agent anti-chute, à la fois pour prévenir la chute des cheveux associée au vieillissement mais aussi comme une thérapie complémentaire pour les troubles liés à la perte des cheveux.

Functions of Arp2/3 Complex in the Dynamics of Epithelial Tissues.

Epithelia are sheets of cells that communicate and coordinate their behavior in order to ensure their barrier function. Among the plethora of proteins involved in epithelial dynamics, actin nucleators play an essential role. The branched actin nucleation complex Arp2/3 has numerous functions, such as the regulation of cell-cell adhesion, intracellular trafficking, the formation of protrusions, that have been well described at the level of individual cells. Here, we chose to focus on its role in epithelial tissue, which is rising attention in recent works. We discuss how the cellular activities of the Arp2/3 complex drive epithelial dynamics and/or tissue morphogenesis. In the first part, we examined how this complex influences cell-cell cooperation at local scale in processes such as cell-cell fusion or cell corpses engulfment. In the second part, we summarized recent papers dealing with the impact of the Arp2/3 complex at larger scale, focusing on different morphogenetic events, including cell intercalation, epithelial tissue closure and epithelial folding. Altogether, this review highlights the central role of Arp2/3 in a diversity of epithelial tissue reorganization.

Transient mTOR inhibition rescues 4-1BB CAR-Tregs from tonic signal-induced dysfunction.

The use of chimeric antigen receptor (CAR)-engineered regulatory T cells (Tregs) has emerged as a promising strategy to promote immune tolerance. However, in conventional T cells (Tconvs), CAR expression is often associated with tonic signaling, which can induce CAR-T cell dysfunction. The extent and effects of CAR tonic signaling vary greatly according to the expression intensity and intrinsic properties of the CAR. Here, we show that the 4-1BB CSD-associated tonic signal yields a more dramatic effect in CAR-Tregs than in CAR-Tconvs with respect to activation and proliferation. Compared to CD28 CAR-Tregs, 4-1BB CAR-Tregs exhibit decreased lineage stability and reduced in vivo suppressive capacities. Transient exposure of 4-1BB CAR-Tregs to a Treg stabilizing cocktail, including an mTOR inhibitor and vitamin C, during ex vivo expansion sharply improves their in vivo function and expansion after adoptive transfer. This study demonstrates that the negative effects of 4-1BB tonic signaling in Tregs can be mitigated by transient mTOR inhibition.

Phagocytosis is coupled to the formation of phagosome-associated podosomes and a transient disruption of podosomes in human macrophages.

Phagocytosis consists in ingestion and digestion of large particles, a process strictly dependent on actin re-organization. Using synchronized phagocytosis of IgG-coated latex beads (IgG-LB), zymosan or serum opsonized-zymosan, we report the formation of actin structures on both phagocytic cups and closed phagosomes in human macrophages. Their lifespan, size, protein composition and organization are similar to podosomes. Thus, we called these actin structures phagosome-associated podosomes (PAPs). Concomitantly to the formation of PAPs, a transient disruption of podosomes occurred at the ventral face of macrophages. Similarly to podosomes, which are targeted by vesicles containing proteases, the presence of PAPs correlated with the maturation of phagosomes into phagolysosomes. The ingestion of LB without IgG did not trigger PAPs formation, did not lead to podosome disruption and maturation to phagolysosomes, suggesting that these events are linked together. Although similar to podosomes, we found that PAPs differed by being resistant to the Arp2/3 inhibitor CK666. Thus, we describe a podosome subtype which forms on phagosomes where it probably serves several tasks of this multifunctional structure.

Arp2/3-dependent mechanical control of morphogenetic robustness in an inherently challenging environment.

Epithelial sheets undergo highly reproducible remodeling to shape organs. This stereotyped morphogenesis depends on a well-defined sequence of events leading to the regionalized expression of developmental patterning genes that finally triggers downstream mechanical forces to drive tissue remodeling at a pre-defined position. However, how tissue mechanics controls morphogenetic robustness when challenged by intrinsic perturbations in close proximity has never been addressed. Using Drosophila developing leg, we show that a bias in force propagation ensures stereotyped morphogenesis despite the presence of mechanical noise in the environment. We found that knockdown of the Arp2/3 complex member Arpc5 specifically affects fold directionality while altering neither the developmental nor the force generation patterns. By combining in silico modeling, biophysical tools, and ad hoc genetic tools, our data reveal that junctional myosin II planar polarity favors long-range force channeling and ensures folding robustness, avoiding force scattering and thus isolating the fold domain from surrounding mechanical perturbations.

Super-resolved live-cell imaging using random illumination microscopy.

Current super-resolution microscopy (SRM) methods suffer from an intrinsic complexity that might curtail their routine use in cell biology. We describe here random illumination microscopy (RIM) for live-cell imaging at super-resolutions matching that of 3D structured illumination microscopy, in a robust fashion. Based on speckled illumination and statistical image reconstruction, easy to implement and user-friendly, RIM is unaffected by optical aberrations on the excitation side, linear to brightness, and compatible with multicolor live-cell imaging over extended periods of time. We illustrate the potential of RIM on diverse biological applications, from the mobility of proliferating cell nuclear antigen (PCNA) in U2OS cells and kinetochore dynamics in mitotic S. pombe cells to the 3D motion of myosin minifilaments deep inside Drosophila tissues. RIM's inherent simplicity and extended biological applicability, particularly for imaging at increased depths, could help make SRM accessible to biology laboratories.

CD70 Deficiency Associated With Chronic Epstein-Barr Virus Infection, Recurrent Airway Infections and Severe Gingivitis in a 24-Year-Old Woman.

Most of the few patients with homozygous CD70 deficiency described to date suffered from EBV-related malignancies in early childhood. We present a woman with CD70 deficiency diagnosed in adulthood. She presented in childhood with recurrent airway infections due to encapsulated bacteria, herpes zoster and a fulminant EBV infection followed by chronic EBV infection with mild lymphoproliferation and severe gingivitis/periodontal disease with high EBV viral load in saliva and gingival plaques as an adult. Up to the age of 24 years she developed no malignancy despite constant EBV viremia since primary EBV infection 15 years previously. Immunologic evaluation in childhood showed hypogammaglobulinemia with impaired polysaccharide responsiveness. She has been stable on immunoglobulin substitution with no further severe viral infections and no bacterial airway infections in adulthood. Targeted panel sequencing at the age of 20 years revealed a homozygous CD70 missense mutation (ENST00000245903.3:c.2T>C). CD70 deficiency was confirmed by absent CD70 expression of B cells and activated T cell blasts. The patient finished high school, persues an academic career and has rarely sick days at college. The clinical course of our patient may help to counsel parents of CD70-deficient patients with regard to prognosis and therapeutic options including haematopoetic stem cell transplantation.

When the Community Silences Disruptive Elements: Multiscale Mechanical Coupling Buffers Morphogenetic Imprecisions.

How the high degree of shape reproducibility is conferred between individuals remains unclear. In this issue of Developmental Cell, Eritano et al. show that tissue-scale mechanical coupling corrects the intrinsic noise of gene expression pattern and tissue mechanics to ensure the high degree of precision of Drosophila cephalic furrow formation.

Impaired lymphocyte function and differentiation in CTPS1-deficient patients result from a hypomorphic homozygous mutation.

Cytidine triphosphate (CTP) synthetase 1 (CTPS1) deficiency is caused by a unique homozygous frameshift splice mutation (c.1692-1G>C, p.T566Dfs26X). CTPS1-deficient patients display severe bacterial and viral infections. CTPS1 is responsible for CTP nucleotide de novo production involved in DNA/RNA synthesis. Herein, we characterized in depth lymphocyte defects associated with CTPS1 deficiency. Immune phenotyping performed in 7 patients showed absence or low numbers of mucosal-associated T cells, invariant NKT cells, memory B cells, and NK cells, whereas other subsets were normal. Proliferation and IL-2 secretion by T cells in response to TCR activation were markedly decreased in all patients, while other T cell effector functions were preserved. The CTPS1T566Dfs26X mutant protein was found to be hypomorphic, resulting in 80%-90% reduction of protein expression and CTPS activity in cells of patients. Inactivation of CTPS1 in a T cell leukemia fully abolished cell proliferation. Expression of CTPS1T566Dfs26X failed to restore proliferation of CTPS1-deficient leukemia cells to normal, except when forcing its expression to a level comparable to that of WT CTPS1. This indicates that CTPS1T566Dfs26X retained normal CTPS activity, and thus the loss of function of CTPS1T566Dfs26X is completely attributable to protein instability. This study supports that CTPS1 represents an attractive therapeutic target to selectively inhibit pathological T cell proliferation, including lymphoma.