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IL-17-producing gamma delta T cells in the pathophysiology of the Central Nervous System
Publication . Cristiano Brigas, Maria Helena; Ribot, Julie Cécile Caroline; Lopes, Luísa Maria Vaqueiro
γδ T cells home to tissues and peripheral lymphoid organs where they strongly contribute to the immune response through the production of IFN-γ or IL-17. IL-17 producing γδ (γδ17) T cells, particularly, can be found in almost all barrier tissues in the body, being critical to protect their hosts against infections while being mostly pathogenic in autoimmune settings. More recently γδ17 T cells have been found to contribute to normal physiological functions of the body. Recently, the notion of “immune privilege” of the central nervous system (CNS) has been revised to integrate its infiltration, at steady state, by lymphatic vessels and immune cells that participate in normal neurophysiology. For instance, murine CD4+ alpha-beta (ab) T cells regulate social behaviour and long-term memory. This notwithstanding, evidence for the role of other immune populations in both physiological and pathological contexts is still scarce. In this thesis, we aimed at understanding whether and how γδ T cell subsets may impact on short-term memory under physiological condition or in a neurodegenerative setting, more specifically in Alzheimer’s disease (AD). We found that foetal-derived Vγ6+ γδ T cell accumulate, at steady state, in the meningeal spaces in the first week of life, persisting throughout the mouse life. Murine γδ T cells are the main source of interleukin (IL)-17 in the meninges, while IFN-γ is mostly provided by their ab counterparts. Meningeal γδ17 T cells did not rely on typical inflammatory signals, shown to be important for their homeostasis and maintenance in other tissues. When tested for memory, mice lacking γδ T cells or IL-17 showed deficits in short-term memory (STM) while retaining a normal long-term memory when compared to littermate controls. In the absence of γδ T cells or IL-17, hippocampal basal transmission and long-term potentiation (LTP) are impaired, possibly due to alterations in the AMPA/NMDA ratio of glutamatergic neurons of these mice. Additionally, IL-17 promotes brain-derived neurotrophic factor (BDNF), whose supplementation is sufficient to recues STM deficits and synaptic impairments observed in mice lacking γδ T cells or IL-17. We added γδ17 T cells to the portfolio of the immune populations infiltrating the central nervous system, at steady state. We suggest a co-evolution of the immune and nervous systems where γδ17 T cells regulate short-term by promoting neuronal synaptic plasticity in the hippocampus.
On the other hand, γδ17 T cells have been pointed as critical initial players in CNS disease progression, namely in models of multiple sclerosis, by contributing to a local immune amplification within the meningeal spaces and altering the stromal microenvironment of the inflamed brain. We therefore questioned whether this cytokine could be implicated in AD progression, where memory loss is one of the main hallmarks. We observed that the tripletransgenic progressive AD-mouse model (3xTg-AD) display a significant increase of γδ17 T cells infiltrating the meninges. This increase was observed at the onset of memory deficits, before the establishment of amyloid-beta (Ab) or Tau pathologies in 3xTg-AD animals. Interestingly, animals treated with anti-IL-17 mAbs did not develop STM deficits observed in the 3xTg-AD animals treated with isotype control. Furthermore, our data suggests that the anti-IL-17 treatment is able to prevent the basal synaptic transmission and LTP impairments that contribute to the early cognitive deficits observed in the 3xTg-AD mice. We postulate that a dysregulation of steady state meningeal IL-17 may influence the onset of AD. This suggests a hypothetic threshold of IL-17 levels, above which CNS inflammation and neurodegeneration can be promoted. This work highlights the potential value of IL-17 as an early biomarker of disease and as a therapeutic target in AD. Additionally, we questioned whether γδ17 T cells could populate other tissues. As the CNS, the testis was described as “immune privilege” and its immune landscape has been neglected. We uncovered that fetal-derived Vγ6+ γδ17 T cells populate the testis of naive mice, expand at puberty and persist throughout life. γδ T cells were the major source of IL-17 in situ and contrary to the meninges, their homeostasis was seemingly dependent on microbial cues and IL-1α/IL-23 signals. Our data indicates that γδ17 T cells contribute to tissue surveillance upon intratesticular bacterial infection. Altogether, this thesis expanded the knowledge in the γδ field by bringing to light two novel locations where Vγ6+ γδ17 T cells reside and contribute to local pathophysiology. We added γδ T cells and IL-17 as immune players to the field of neuroimmunology, by showing they regulate short-term memory and neuronal connectivity. Additionally, we suggest a dual role for IL-17 in memory. Finding a balance between the protective and pathological levels of IL-17 might open new immunotherapeutic strategies for neurodegenerative diseases, namely, AD.
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PD/BD/114103/2015