Alpha-adducin (Add1) is a critical component of the actin-spectrin network in erythrocytes, acting to cap the fast-growing, barbed ends of actin filaments, and recruiting spectrin to these junctions. Add1 is highly expressed in T cells, but its role in T-cell activation has not been examined. Using a conditional knockout model, we show that Add1 is necessary for complete activation of CD4+ T cells in response to low levels of antigen but is dispensable for CD8+ T cell activation and response to infection. Surprisingly, costimulatory signals through CD28 were completely abrogated in the absence of Add1. This study is the first to examine the role of actin-capping in T cells, and it reveals a previously unappreciated role for the actin cytoskeleton in regulating costimulation.
Background
Inborn errors of immunity (IEI) are a group of genetic disorders that impair the immune system, with over 400 genes described so far, and hundreds more to be discovered. To facilitate the search for new genes, we need a way to prioritize among all the genes in the genome those most likely to play an important role in immunity.
Results
Here we identify a new list of genes by linking known IEI genes to new ones by using open-source databases of protein-protein interactions, post-translational modifications, and transcriptional regulation. We analyze this new set of 2,530 IEI-related genes for their tolerance of genetic variation and by their expression levels in various immune cell types.
Conclusions
By merging genes derived from protein interactions of known IEI genes with transcriptional data, we offer a new list of candidate genes that may play a role in as-yet undiscovered IEIs.
Background: The search for a single, pathogenic genetic variant in a patient suspected to have a monogenic inborn error of immunity (IEI) often reveals a multitude of rare variants of unknown significance (VUS). Distinguishing which VUS is disease-causing versus the irrelevant, rare variants from the genetic background is slow and difficult. Advances in gene editing technology, particularly CRISPR/Cas9, promise to accelerate the timeline for the development of single-variant animal models, thus affording an experimental system for validating new genes and their variants.
Objective: We sought to demonstrate a proof-of-concept of using CRISPR/Cas9 in human hematopoietic stem cells (hHSC) to develop of humanized mice bearing a hematopoietic deficiency in signal transducer and activator 1 (STAT1).
Methods: Using CRISPR/Cas9, we introduced indels into the STAT1 gene of hHSCs and implanted them into immunodeficient mice. The reconstituted immune systems were assessed by flow cytometry.
Results: Mice transplanted with cells edited to eliminate STAT1 developed human immune systems with diverse cell phenotypes. Lymphocytes from these reconstituted mice showed low expression of STAT1 protein and diminished phosphorylation of STAT1 in response to interferon stimulation. These data mirror the impaired, but not abolished, response to interferons seen in human partial STAT1 deficiency. CRISPR/Cas9 genome editing techniques can be used to rapidly and inexpensively create functional, humanized models of primary immune deficiencies.
Background: The inborn errors of immunity (IEI) that include defective antibody responses are clinically heterogenous, especially the common variable immunodeficiency (CVID) phenotype that includes low immunoglobulin levels and impaired humoral responses to antigens. Beyond recurrent infections, many with the CVID phenotype develop non-infectious complications (NICs), including autoimmunity and lymphoproliferation, that confer a high rate of morbidity and mortality. At present, it is unknown what genetic and functional factors predispose patients to NICs.
Objective: We aimed to discover the pathobiology underlying complicated CVID (CVIDc).
Methods: In a heterogenous group of 12 CVIDc patients, we conducted whole exome sequencing and high-throughput signaling assays by multiplexed phospho-mass cytometry. The immune deficiency and dysregulation activity (IDDA) score was used to determine the burden of NICs in individual patients. We integrated polygenic risk scores to determine the role of common background variants in the pathogenesis of CVIDc.
Results: In CVID patients with high IDDA scores, there was aberrant increased phosphorylation of STAT1 and STAT3 upon stimulation with IL-10 or IL-21. Furthermore, common variants related to high eosinophil count and allergy/eczema confer a higher likelihood of autoimmunity in CVID.
Conclusion: Variants in loci related to high eosinophil count/function and over-reactive IL-10 signaling are associated with the development of autoimmune disease and NICs in CVID.
Clinical implications: It may be possible to manage CVIDc through modulating IL-10 and IL-21 signaling pathways. Polygenic risk scoring may predict the development of autoimmune complications in CVID patients.
Inborn errors of immunity (IEI) are a group of genetic disorders that impair the immune system, with over 400 genes described so far, and hundreds more to be discovered. To facilitate the search for new genes, we need a way to prioritize among all the genes in the genome those most likely to play an important role in immunity. Here we identify a new list of genes by linking known IEI genes to new ones by using open-source databases of protein-protein interactions, post-translational modifications, and transcriptional regulation. We analyze this new set of 2,530 IEI-related genes for their tolerance of genetic variation and by their expression levels in various immune cell types.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.