Ribeiro M, Brigas HC, Temido-Ferreira M, Pousinha PA, Regen T, Santa C, Coelho JE, Marques-Morgado I, Valente CA, Omenetti S, Stockinger B, Waisman A, Manadas B, Lopes LV, Silva-Santos B, Ribot JC. Meningeal γδ T cell-derived IL-17 controls synaptic plasticity and short-term memory. Sci Immunol. 2019 Oct 11;4(40) PubMed.

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  1. For centuries, the brain was viewed as an immune-privileged organ fully isolated from the periphery and the interactions between the immune system and central nervous system (CNS) were classically associated with pathological conditions.

    This traditional concept has recently come under the spotlight by several paradigm-shift studies providing evidence that meninges, a triple-layer membrane surrounding the CNS, harbor a rich arsenal of immune cells that can influence brain function under homeostasis (summarized in Kipnis, 2016, and Aug 2018 Scientific American article). 

    Inspired by previous literature linking meningeal T cells and homeostatic brain functions, Ribeiro and colleagues describe now a meningeal population of γδ T cells highly biased toward IL-17A production.

    Given this unique anatomical location, the authors hypothesized that IL-17A-derived from the meningeal spaces would have crucial effects on the CNS regulation under steady state. By using the Y-maze spontaneous alternation paradigm as a test for measuring short-term memory in mice, the authors observed a cognitive deficit in the absence of either γδ T cells or IL-17A. In order to explain the mechanisms underlying these behavioral changes, the authors found a deficit in synaptic plasticity in the absence of IL-17A and suggested the promotion of brain-derived neurotrophic factor (BDNF) as a key factor for controlling working memory.

    Several aspects remain poorly understood and future studies are necessary to fully address the crosstalk between meningeal γδ T cells and brain function. Which signals are crucial for the recruitment and activation of γδ T cells into the meningeal spaces? What is the spatial location of these cells? How is meningeal IL-17A capable of modulating BDNF expression in the parenchyma? Since the authors could not observe similar phenotype after the conditional deletion of IL-17R in astrocytes and microglia, what is actually the cellular target for IL-17A in the brain?

    Unraveling these connections may improve our understanding of this emerging field of neuroimmunology and may provide new opportunities for the manipulation of meningeal spaces in order to benefit healthy and diseased brain.

    References:

    Kipnis J. Multifaceted interactions between adaptive immunity and the central nervous system. Science. 2016 Aug 19;353(6301):766-71. PubMed.

    View all comments by Kalil Alves de Lima

  2. This seminal work demonstrates a bridge between innate and adaptive immune influences on the CNS. Over the past few years, many studies have emphasized the critical role of mononuclear phagocytes and conventional T cell (CD4+/CD8+) involvement in learning and memory. The presence of meningeal-resident γδ IL-17 producing T cells from birth raises many intriguing questions as to their later role in a chronic neuroinflammatory setting such as Alzheimer’s disease.

    It is becoming increasingly apparent that IL-17-producing T cells influence the gut-brain axis, autism, and depression (Beurel and Lowell, 2018). This is not surprising, as IL-17 has long been known to be involved in leukocyte trafficking, blood-brain barrier integrity, and inflammation. Moreover, we know that γδ IL-17 T cells predominate at the early stages of inflammatory responses, and have the potential to orchestrate protective or detrimental crosstalk between the innate and adaptive immune compartments as shown in multiple sclerosis, stroke, and Parkinson’s disease.

    This important work highlights the critical intersection between adaptive and innate immunity in the neurological context.

    References:

    Beurel E, Lowell JA. Th17 cells in depression. Brain Behav Immun. 2018 Mar;69:28-34. Epub 2017 Aug 3 PubMed.

    View all comments by Terrence Town

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