Meningeal γδ T Cells Regulate Anxiety-Like Behavior via IL-17a Signaling in Neurons

Lima, Kalil Alves de; Rustenhoven, Justin; Mesquita, Sandro Dá; Wall, Morgan; Salvador, Andrea Francesca; Smirnov, Igor; Cebinelli, Guilherme Cesar Martelossi; Mamuladze, Tornike; Baker, Wendy; Papadopoulos, Zachary; Lopes, M. Beatriz S.; Cao, William S.; Xie, Xinmin; Herz, Jasmin; Kipnis, Jonathan

doi:10.1016/j.biopsych.2021.02.177

Cited by 27 publications

(50 citation statements)

References 7 publications

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“…A role for T-cells in modulating brain development has been established, with previous studies showing changes in the volume of several brain regions in TCR β–/–δ–/– mice [ 13 ], paralleled by decreased anxiety-like behaviour, but elevated basal cortisol in TCR β–/–δ–/– mice [ 13 , 14 ]. Further, IL-17a released by meningeal γδ T-cells have also been shown to modulate anxiety-like behavior [ 2 ], and effect that may be mediated by microglia by inducing phagocytosis of neural progenitor cells [ 42 ]. The observation that both T-cells [ 43 ] and gut bacteria [ 44 ] are necessary to support microglia maturation suggests that the next key step is to determine mechanistically how these central immune cells mediate the brain abnormalities observed in the absence of a functional T-cell-microbe crosstalk.…”

Section: Discussionmentioning

confidence: 99%

“…While the current study did not directly examine IL17, evidence for a dysfunctional T-cell-microbe crosstalk in CNS disorders was provided in the context of experimental autoimmune encephalomyelitis (EAE, a model of multiple sclerosis, [ 46 ]) and maternal immune activation (MIA, a model of autism, [ 47 , 48 , 49 ]), where induction of the T helper 17 (Th17)/IL-17a pathway by members of the gut microbiota elicited cortical and behavioral abnormalities. In the absence of neuronal IL-17a signalling, an upregulation of genes involved in GABA neurotransmission was also observed [ 2 ]. While not directly tested here, this is consistent with the changes in GABA in the present study in the frontal cortex, hippocampus and hypothalamus.…”

Section: Discussionmentioning

confidence: 99%

“…Importantly, a potential role for the microbiome and microbe-immune signalling pathways in neurodevelopment has emerged [ 1 ]. T-lymphocytes are a key mediator of this crosstalk [ 2 , 3 ]. While the impact of the gut microbiome on the development of the immune system is well-established, a clear understanding of how microbiota-immune signalling impacts neurodevelopment is still in its infancy.…”

Section: Introductionmentioning

confidence: 99%

“…These behavioral and physiological alterations were paralleled by changes in the volume of several brain regions [ 13 ]. Recently, γδ T-cells have been shown to modulate anxiety-like behavior by releasing IL-17a at the meninges and eliciting transcriptional changes in neurons [ 2 ]. Together, these studies support a link between T-cell-microbe crosstalk and the behavioral phenotype.…”

Section: Introductionmentioning

confidence: 99%

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Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome

Caspani

Green

Swann

et al. 2022

IJMS

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Cross-talk between the immune system and the brain is essential to neuronal development, neuronal excitability, neuroplasticity, and neurotransmission. Gut microbiota are essential to immune system development and immune function; hence, it is essential to consider more broadly the microbiota-immune-brain axis in neurodevelopment. The gut, brain, and microbial metabolomes obtained from C57Bl/6 and T-cell-deficient mice across four developmental timepoints (postnatal day 17, 24, 28, and 84) were studied by 1H NMR spectroscopy. 16S rRNA gene sequencing was performed on cecal and fecal samples. In the absence of T-cells, the developmental trajectory of the gut microbiota and of the host’s metabolic profile was altered. The novel insights from this work include (1) the requirement of functional T-cells for the normal trajectory of microbiotal development and the metabolic maturation of the supra-organism, (2) the potential role for Muribaculaceae taxa in modulating the cecal availability of metabolites previously implicated with a role in the gut-brain axis in T-cell deficient mice, and (3) the impact of T-cell-deficiency on central levels of neuroactive metabolites.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome

Caspani

Green

Swann

et al. 2022

IJMS

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“…Within the brain, IL17RA is expressed by various types of cells and previous in vitro and in vivo studies in mouse models have shown that IL17RA/IL-17a signaling exerts effects on neural progenitor cells (NPCs) ( Li et al, 2013 ; Tfilin and Turgeman, 2019 ), neurons ( Liu et al, 2014 ; Tfilin and Turgeman, 2019 ; de Lima et al, 2020 ), astrocytes ( Kostic et al, 2017 ), oligodendrocytes ( Wang et al, 2017 ), and microglia ( Sasaki et al, 2020 ). However, the mechanisms by which IL-17a affects the human developing brain and the specific cell types that are affected by IL-17a signaling to contribute to ASD-related deficits are still poorly understood.…”

Section: Introductionmentioning

confidence: 99%

Interleukin-17a Induces Neuronal Differentiation of Induced-Pluripotent Stem Cell-Derived Neural Progenitors From Autistic and Control Subjects

et al. 2022

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Prenatal exposure to maternal immune activation (MIA) has been suggested to increase the probability of autism spectrum disorder (ASD). Recent evidence from animal studies indicates a key role for interleukin-17a (IL-17a) in promoting MIA-induced behavioral and brain abnormalities reminiscent of ASD. However, it is still unclear how IL-17a acts on the human developing brain and the cell types directly affected by IL-17a signaling. In this study, we used iPSC-derived neural progenitor cells (NPCs) from individuals with ASD of known and unknown genetic cause as well as from neurotypical controls to examine the effects of exogenous IL-17a on NPC proliferation, migration and neuronal differentiation, and whether IL-17a and genetic risk factors for ASD interact exacerbating alterations in NPC function. We observed that ASD and control NPCs endogenously express IL-17a receptor (IL17RA), and that IL-17a/IL17RA activation modulates downstream ERK1/2 and mTORC1 signaling pathways. Exogenous IL-17a did not induce abnormal proliferation and migration of ASD and control NPCs but, on the other hand, it significantly increased the expression of synaptic (Synaptophysin-1, Synapsin-1) and neuronal polarity (MAP2) proteins in these cells. Also, as we observed that ASD and control NPCs exhibited similar responses to exogenous IL-17a, it is possible that a more inflammatory environment containing other immune molecules besides IL-17a may be needed to trigger gene-environment interactions during neurodevelopment. In conclusion, our results suggest that exogenous IL-17a positively regulates the neuronal differentiation of human NPCs, which may disturb normal neuronal and synaptic development and contribute to MIA-related changes in brain function and behavior.

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Gut instincts in neuroimmunity from the eighteenth to twenty-first centuries

Nguyen

Palm

2022

Semin Immunopathol

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In the past two decades, work on the microbiota-gut-brain axis has led to a renewed appreciation for the interconnectedness between body systems in both clinical and scientific circles. In the USA alone, millions of adults are burdened with non-communicable chronic diseases whose putative etiologies were previously thought to be restricted to either the gut or brain, such as inflammatory bowel disease, irritable bowel syndrome, Parkinson’s and Alzheimer’s disease, and autism spectrum disorder. However, the recent explosion of research into the impacts of the gut microbiome on diverse aspects of human health has revealed the potentially critical importance of reciprocal interactions between the gut microbiota, the immune system, and the brain in diverse diseases and disorders. In this review, we revisit the history of gut-brain interactions in science and medicine, which dates back to at least the eighteenth century, and outline how concepts in this field have shifted and evolved across eras. Next, we highlight the modern resurgence of gut-brain axis research, focusing on neuro-immune-microbiota interactions and recent progress towards a mechanistic understanding of the diverse impacts of the microbiome on human health. Finally, we offer a forward-looking perspective on the future of microbiota-gut-brain research, which may eventually reveal new paths towards the treatment of diverse diseases influenced by the complex connections between the microbiota and the brain.

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Meningeal γδ T Cells Regulate Anxiety-Like Behavior via IL-17a Signaling in Neurons

Cited by 27 publications

References 7 publications

Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome

Microbe-Immune Crosstalk: Evidence That T Cells Influence the Development of the Brain Metabolome

Interleukin-17a Induces Neuronal Differentiation of Induced-Pluripotent Stem Cell-Derived Neural Progenitors From Autistic and Control Subjects

Gut instincts in neuroimmunity from the eighteenth to twenty-first centuries

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