γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde

Li, Yunxuan; Zhang, Yixi; Zeng, Xun

doi:10.3389/fimmu.2021.656097

Cited by 10 publications

(11 citation statements)

References 139 publications

(191 reference statements)

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“…Most striking is GABRG2, which shows marginal expression in all WBCs except for T.gd cells (γδ T cells) in COVID-19 patients, where a >20-fold increase in expression was found compared with controls. γδ T cells form a minor population of WBCs, but they increase dramatically during infections and play a key role in autoimmunity and immune surveillance 114, 115 . Perhaps more importantly from the perspective of PANS is the finding that γδ T cells are found in meninges where they secrete the proinflammatory cytokine IL-17a and participate in the development of anxiety-like behavior in mice 116 .…”

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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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

View full text Add to dashboard Cite

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“…The IL-17 family consists of several cytokines that participate in both acute and chronic inflammatory responses [ 50 ]. IL-17 is expressed by both Th17 and γδ T cells and is detrimental in stroke [ 51 , 52 ]. In addition to recruited immune cells of the immune system, CNS-resident astrocytes and microglia are sources of IL-17 production during damage progression in the ischemic brain [ 50 ].…”

Section: Discussionmentioning

confidence: 99%

“…The IL-17 family consists of several cytokines that participate in both acute and chronic inflammatory responses [50]. IL-17 is expressed by both Th17 and γδ T cells and is detrimental in stroke [51,52]. Figure 9: Epimedium reduced the oxidative stress in rats with ischemic stroke.…”

Section: Discussionmentioning

confidence: 99%

Molecular Mechanism of Epimedium Extract against Ischemic Stroke Based on Network Pharmacology and Experimental Validation

You

Xiang

et al. 2022

Oxidative Medicine and Cellular Longevity

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Ischemic stroke exhibits high morbidity, disability, and mortality, and treatments for ischemic stroke are limited despite intensive research. The potent neuroprotective benefits of Epimedium against ischemic stroke have gained lots of interest. Nevertheless, systematic research on the direct role and mechanisms of Epimedium in ischemic stroke is still lacking. Network pharmacology analysis coupled with experimental verification was utilized to systematically evaluate the potential pharmacological mechanism of Epimedium against ischemic stroke. The TCMSP database was used to mine the bioactive ingredients and Epimedium’s targets. The DrugBank, OMIM, and GeneCards databases were employed to identify potential targets of ischemic stroke. GO and KEGG pathway analyses were also carried out. The interaction between active components and hub targets was confirmed via molecular docking. An experimental ischemic stroke model was used to evaluate the possible therapeutic mechanism of Epimedium. As a result, 23 bioactive compounds of Epimedium were selected, and 30 hub targets of Epimedium in its function against ischemic stroke were identified, and molecular docking results demonstrated good binding. The IL-17 signaling pathway was revealed as a potentially significant pathway, with the NF-κB and MAPK/ERK signaling pathways being involved. Furthermore, in vivo experiments demonstrated that Epimedium treatment could improve neurological function and reduce infarct volume. Additionally, Epimedium reduced the activation of microglia and astrocytes in both the ischemic penumbra of the hippocampus and cerebral cortex following ischemic stroke. Western blot and RT–qPCR analyses demonstrated that Epimedium not only depressed the expression of IL-1β, TNF-α, IL-6, and IL-4 but also inhibited the NF-κB and MAPK/ERK signaling pathways. This study applied network pharmacology and in vivo experiment to explore possible mechanism of Epimedium’s role against ischemic stroke, which provides insight into the treatment of ischemic stroke.

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“…In neurotrauma, γδ T cells are one group of the earliest immune cells arriving at the injury site ( 15 – 17 ). Moreover, γδ T cells in the meninges regulate the inflammatory responses during massive CNS injury by secreting typical immune factors: IFN-γ and IL-17 ( 18 – 20 ). Therefore, we assume that γδ T cells may be involved in the immune response and influence the pathological process in the brain after CMBs.…”

Section: Introductionmentioning

confidence: 99%

γδ T cells recruitment and local proliferation in brain parenchyma benefit anti-neuroinflammation after cerebral microbleeds

Yang

et al. 2023

Front. Immunol.

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BackgroundCerebral microbleeds (CMBs) are an early sign of many neurological disorders and accompanied by local neuroinflammation and brain damage. As important regulators of immune response and neuroinflammation, the biological behavior and role of γδ T cells after CMBs remain largely unknown.MethodsWe made a spot injury of microvessel in the somatosensory cortex to mimic the model of CMBs by two-photon laser and in vivo tracked dynamical behaviors of γδ T cells induced by CMBs using TCR-δGFP transgenic mice. Biological features of γδ T cells in the peri-CMBs parenchyma were decoded by flow cytometry and Raman spectra. In wildtype and γδ T cell-deficient mice, neuroinflammation and neurite degeneration in the peri-CMBs cortex were studied by RNAseq, immunostaining and in vivo imaging respectively.ResultsAfter CMBs, γδ T cells in the dural vessels were tracked to cross the meningeal structure and invade the brain parenchyma in a few days, where the division process of γδ T cells were captured. Parenchymal γδ T cells were highly expressed by CXCR6 and CCR6, similar to meningeal γδ T cells, positive for IL-17A and Ki67 (more than 98%), and they contained abundant substances for energy metabolism and nucleic acid synthesis. In γδ T cell-deficient mice, cortical samples showed the upregulation of neuroinflammatory signaling pathways, enhanced glial response and M1 microglial polarization, and earlier neuronal degeneration in the peri-CMBs brain parenchyma compared with wildtype mice.ConclusionCMBs induce the accumulation and local proliferation of γδ T cells in the brain parenchyma, and γδ T cells exert anti-neuroinflammatory and neuroprotective effects at the early stage of CMBs.

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γδ T Cells Participating in Nervous Systems: A Story of Jekyll and Hyde

Cited by 10 publications

References 139 publications

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

Molecular Mechanism of Epimedium Extract against Ischemic Stroke Based on Network Pharmacology and Experimental Validation

γδ T cells recruitment and local proliferation in brain parenchyma benefit anti-neuroinflammation after cerebral microbleeds

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