Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells

Helgeland, Hanna; Gabrielsen, Ingvild; Akselsen, Helle; Sundaram, Arvind; Flåm, Siri Tennebø; Lie, Benedicte A.

doi:10.21203/rs.2.18314/v1

Cited by 4 publications

(5 citation statements)

References 45 publications

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“…Myeloid cells were defined by canonical markers Cd11b and Cd74 (28), but other noncanonical markers were also observed, including Myo1f (29) and Tgfb (30). Lymphocytes showed a similar mix of broad and specific expression patterns of cell type markers, with expression of pan-lymphocyte marker Il18r1, T lymphocyte marker Prkcq, and cytotoxic T cell marker Cd8b (31)(32)(33). Last, we detected a cluster of MSCs/stromal cells that expressed both broad mesenchymal cell markers Rbms3 and Tshz2 and stem/stromal cell markers Prkg1 and Gpc6 (fig.…”

Section: Resultsmentioning

confidence: 99%

XYZeq: Spatially resolved single-cell RNA sequencing reveals expression heterogeneity in the tumor microenvironment

et al. 2021

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Single-cell RNA sequencing (scRNA-seq) of tissues has revealed remarkable heterogeneity of cell types and states but does not provide information on the spatial organization of cells. To better understand how individual cells function within an anatomical space, we developed XYZeq, a workflow that encodes spatial metadata into scRNA-seq libraries. We used XYZeq to profile mouse tumor models to capture spatially barcoded transcriptomes from tens of thousands of cells. Analyses of these data revealed the spatial distribution of distinct cell types and a cell migration-associated transcriptomic program in tumor-associated mesenchymal stem cells (MSCs). Furthermore, we identify localized expression of tumor suppressor genes by MSCs that vary with proximity to the tumor core. We demonstrate that XYZeq can be used to map the transcriptome and spatial localization of individual cells in situ to reveal how cell composition and cell states can be affected by location within complex pathological tissue.

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Section: Resultsmentioning

confidence: 99%

XYZeq: Spatially resolved single-cell RNA sequencing reveals expression heterogeneity in the tumor microenvironment

et al. 2021

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“…Germline loss of function mutations in the kinase domain are found in several inherited cancer syndromes 39, 40 . The protein encoded by CHK2 is expressed in T-cells and regulates IL-2 expression 41 . The rare variant we identified, T410fsX14, is a truncating mutation in the distal end of the kinase domain and is probably a loss-of-function mutation.…”

Section: Resultsmentioning

confidence: 99%

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Trifiletti¹,

Manusama

et al. 2021

Preprint

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Pediatric acute onset neuropsychiatric syndrome (PANS) is viewed as an autoimmune/autoinflammatory condition characterized by the abrupt onset of severe neurological and psychiatric symptoms, in particular obsessive-compulsive disorder (OCD), tics, anxiety, mood swings, irritability, and restricted eating, often triggered by infections. However, direct evidence of autoimmunity, infections, or a proinflammatory state is often lacking, and there is no unifying pathogenic pathway. This could be due to underlying genetic heterogeneity, which could lead to the development of PANS through different cellular and molecular pathways. Unfortunately, little is known about the genetic basis of PANS. Consequently, we carried out whole exome sequencing (WES) on a U.S. cohort of 386 cases who met diagnostic criteria for PANS, including 133 family triads, and whole genome sequencing (WGS) on ten cases from the European Union, who were selected for WGS because of severe PANS symptoms. We focused on identifying potentially deleterious genetic variants that were either de novo or ultra-rare with a minor allele frequency (MAF) < 0.001. Candidate mutations were found in 11 genes: PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1 in a total of 20 cases, which included two sets of siblings, and two or more unrelated subjects with ultra-rare variants in SGCE, NLRC4, RAG1, and SHANK3. The PANS candidate genes we identified separate into two broad functional categories. One group regulates peripheral innate and adaptive immune responses (e.g., PPM1D, CHK2, NLRC4, RAG1, PLCG2), some of which also influence microglia function. Another is expressed primarily at neuronal synapses or directly modulates synaptic function (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). These neuronal PANS candidate genes are often mutated in autism spectrum disorder, developmental disorders, and myoclonus-dystonia. In fact, eight out of 20 cases in this study developed PANS superimposed on a preexisting neurodevelopmental disorder. There is, however, clinical overlap between these two groups and some crossover expression (e.g., some neuronal genes are expressed in immune cells and vice versa) that diminishes the neuronal/immune dichotomy. Genes in both categories are also highly expressed in the enteric nervous system, and in the choroid plexus and brain vasculature, suggesting they might contribute to a breach in the blood-CSF barrier and blood-brain barrier (BBB) that would permit the entry of autoantibodies, inflammatory cytokines, chemokines, prostaglandins, and autoantibodies into the brain. Thus, PANS is a genetically heterogeneous condition that can occur as a stand-alone neuropsychiatric condition or co-morbid with neurodevelopmental disorders, with candidate genes functioning at several levels of the neuroinflammatory axis.

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“…Like PPM1D, CHK2 also codes for a regulator of the DNA repair response by phosphorylating p53 15,55 . It also regulates IL-2 expression in T-cells 56 , and Chk2 inactivation in mouse B cells leads to decreased Ig hypermutation, Ig class switching and immune dysregulation 57 .…”

Section: Discussionmentioning

confidence: 99%

Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing

Trifiletti¹,

Lachman

Manusama

et al. 2022

Sci Rep

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Abrupt onset of severe neuropsychiatric symptoms including obsessive–compulsive disorder, tics, anxiety, mood swings, irritability, and restricted eating is described in children with Pediatric Acute-Onset Neuropsychiatric Syndrome (PANS). Symptom onset is often temporally associated with infections, suggesting an underlying autoimmune/autoinflammatory etiology, although direct evidence is often lacking. The pathological mechanisms are likely heterogeneous, but we hypothesize convergence on one or more biological pathways. Consequently, we conducted whole exome sequencing (WES) on a U.S. cohort of 386 cases, and whole genome sequencing (WGS) on ten cases from the European Union who were selected because of severe PANS. We focused on identifying potentially deleterious genetic variants that were de novo or ultra-rare (MAF) < 0.001. Candidate mutations were found in 11 genes (PPM1D, SGCE, PLCG2, NLRC4, CACNA1B, SHANK3, CHK2, GRIN2A, RAG1, GABRG2, and SYNGAP1) in 21 cases, which included two or more unrelated subjects with ultra-rare variants in four genes. These genes converge into two broad functional categories. One regulates peripheral immune responses and microglia (PPM1D, CHK2, NLRC4, RAG1, PLCG2). The other is expressed primarily at neuronal synapses (SHANK3, SYNGAP1, GRIN2A, GABRG2, CACNA1B, SGCE). Mutations in these neuronal genes are also described in autism spectrum disorder and myoclonus-dystonia. In fact, 12/21 cases developed PANS superimposed on a preexisting neurodevelopmental disorder. Genes in both categories are also highly expressed in the enteric nervous system and the choroid plexus. Thus, genetic variation in PANS candidate genes may function by disrupting peripheral and central immune functions, neurotransmission, and/or the blood-CSF/brain barriers following stressors such as infection.

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Transcriptome profiling of human thymic CD4+ and CD8+ T cells compared to primary peripheral T cells

Cited by 4 publications

References 45 publications

XYZeq: Spatially resolved single-cell RNA sequencing reveals expression heterogeneity in the tumor microenvironment

XYZeq: Spatially resolved single-cell RNA sequencing reveals expression heterogeneity in the tumor microenvironment

Identification of ultra-rare genetic variants in Pediatric Acute Onset Neuropsychiatric Syndrome (PANS) by exome and whole genome sequencing

Identification of ultra-rare genetic variants in pediatric acute onset neuropsychiatric syndrome (PANS) by exome and whole genome sequencing

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