RESUMEN
Neuroinflammation in patients with Alzheimer's disease (AD) and related mouse models has been recognized for decades, but the contribution of the recently described meningeal immune population to AD pathogenesis remains to be addressed. Here, using the 3xTg-AD model, we report an accumulation of interleukin-17 (IL-17)-producing cells, mostly γδ T cells, in the brain and the meninges of female, but not male, mice, concomitant with the onset of cognitive decline. Critically, IL-17 neutralization into the ventricles is sufficient to prevent short-term memory and synaptic plasticity deficits at early stages of disease. These effects precede blood-brain barrier disruption and amyloid-beta or tau pathology, implying an early involvement of IL-17 in AD pathology. When IL-17 is neutralized at later stages of disease, the onset of short-memory deficits and amyloidosis-related splenomegaly is delayed. Altogether, our data support the idea that cognition relies on a finely regulated balance of "inflammatory" cytokines derived from the meningeal immune system.
Asunto(s)
Enfermedad de Alzheimer/metabolismo , Conducta Animal , Encéfalo/metabolismo , Cognición , Mediadores de Inflamación/metabolismo , Interleucina-17/metabolismo , Linfocitos Intraepiteliales/metabolismo , Enfermedades Neuroinflamatorias/metabolismo , Sinapsis/metabolismo , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/prevención & control , Enfermedad de Alzheimer/psicología , Animales , Antiinflamatorios/farmacología , Anticuerpos Monoclonales/farmacología , Anticuerpos Neutralizantes/farmacología , Conducta Animal/efectos de los fármacos , Encéfalo/efectos de los fármacos , Encéfalo/patología , Cognición/efectos de los fármacos , Modelos Animales de Enfermedad , Femenino , Mediadores de Inflamación/antagonistas & inhibidores , Interleucina-17/antagonistas & inhibidores , Linfocitos Intraepiteliales/efectos de los fármacos , Masculino , Memoria a Corto Plazo , Ratones de la Cepa 129 , Ratones Transgénicos , Enfermedades Neuroinflamatorias/patología , Enfermedades Neuroinflamatorias/prevención & control , Enfermedades Neuroinflamatorias/psicología , Plasticidad Neuronal , Sinapsis/efectos de los fármacos , Sinapsis/patologíaRESUMEN
γδT cells represent the majority of lymphocytes in several mucosal tissues where they contribute to tissue homoeostasis, microbial defence and wound repair. Here we characterise a population of interleukin (IL) 17-producing γδ (γδ17) T cells that seed the testis of naive C57BL/6 mice, expand at puberty and persist throughout adulthood. We show that this population is foetal-derived and displays a T-cell receptor (TCR) repertoire highly biased towards Vγ6-containing rearrangements. These γδ17 cells were the major source of IL-17 in the testis, whereas αß T cells mostly provided interferon (IFN)-γ in situ. Importantly, testicular γδ17 cell homoeostasis was strongly dependent on the microbiota and Toll-like receptor (TLR4)/IL-1α/IL-23 signalling. We further found that γδ17 cells contributed to tissue surveillance in a model of experimental orchitis induced by intra-testicular inoculation of Listeria monocytogenes, as Tcrδ-/- and Il17-/- infected mice displayed higher bacterial loads than wild-type (WT) controls and died 3 days after infection. Altogether, this study identified a previously unappreciated foetal-derived γδ17 cell subset that infiltrates the testis at steady state, expands upon puberty and plays a crucial role in local tissue immune surveillance.
Asunto(s)
Microbiota/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Maduración Sexual/inmunología , Testículo/inmunología , Testículo/metabolismo , Células Th17/inmunología , Células Th17/metabolismo , Animales , Biomarcadores , Citocinas , Inmunohistoquímica , Vigilancia Inmunológica , Inmunofenotipificación , Interleucina-17/biosíntesis , Interleucina-23/metabolismo , Masculino , Ratones , Ratones Transgénicos , Espermatogénesis , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismoRESUMEN
The notion of "immune privilege" of the brain has been revised to accommodate its infiltration, at steady state, by immune cells that participate in normal neurophysiology. However, the immune mechanisms that regulate learning and memory remain poorly understood. Here, we show that noninflammatory interleukin-17 (IL-17) derived from a previously unknown fetal-derived meningeal-resident γδ T cell subset promotes cognition. When tested in classical spatial learning paradigms, mice lacking γδ T cells or IL-17 displayed deficient short-term memory while retaining long-term memory. The plasticity of glutamatergic synapses was reduced in the absence of IL-17, resulting in impaired long-term potentiation in the hippocampus. Conversely, IL-17 enhanced glial cell production of brain-derived neurotropic factor, whose exogenous provision rescued the synaptic and behavioral phenotypes of IL-17-deficient animals. Together, our work provides previously unknown clues on the mechanisms that regulate short-term versus long-term memory and on the evolutionary and functional link between the immune and nervous systems.