RESUMEN
The adaptive arm of the immune system has been suggested as an important factor in brain function. However, given the fact that interactions of neurons or glial cells with T lymphocytes rarely occur within the healthy CNS parenchyma, the underlying mechanism is still a mystery. Here we found that at the interface between the brain and blood circulation, the epithelial layers of the choroid plexus (CP) are constitutively populated with CD4(+) effector memory cells with a T-cell receptor repertoire specific to CNS antigens. With age, whereas CNS specificity in this compartment was largely maintained, the cytokine balance shifted in favor of the T helper type 2 (Th2) response; the Th2-derived cytokine IL-4 was elevated in the CP of old mice, relative to IFN-γ, which decreased. We found this local cytokine shift to critically affect the CP epithelium, triggering it to produce the chemokine CCL11 shown to be associated with cognitive dysfunction. Partial restoration of cognitive ability in aged mice, by lymphopenia-induced homeostasis-driven proliferation of memory T cells, was correlated with restoration of the IL-4:IFN-γ ratio at the CP and modulated the expression of plasticity-related genes at the hippocampus. Our data indicate that the cytokine milieu at the CP epithelium is affected by peripheral immunosenescence, with detrimental consequences to the aged brain. Amenable to immunomodulation, this interface is a unique target for arresting age-related cognitive decline.
Asunto(s)
Envejecimiento/inmunología , Envejecimiento/patología , Encéfalo/inmunología , Encéfalo/patología , Plexo Coroideo/inmunología , Plexo Coroideo/patología , Células Th2/inmunología , Células Th2/patología , Inmunidad Adaptativa , Animales , Barrera Hematoencefálica/inmunología , Barrera Hematoencefálica/patología , Proliferación Celular , Epitelio/inmunología , Epitelio/patología , Hipocampo/inmunología , Hipocampo/patología , Memoria Inmunológica , Linfopenia/inmunología , Linfopenia/patología , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Neuroinmunomodulación , Receptores de Interferón/deficiencia , Receptores de Interferón/genética , Receptor de Interferón gammaRESUMEN
An organism's behavior is determined by the way it senses and perceives the surrounding environment, and by its responses to these stimuli. The major factors known to affect the behavioral response to an event are genetic background, environmental factors, and past experiences, and their imprinting on the relevant brain circuits. Recently, circulating immune cells were introduced as novel players into this system. It was proposed that the brain and circulating immune cells engage in a continuous dialogue that takes place within the brain's territory, though outside the parenchyma (occurring within the brain's borders - the choroid plexi, the brain meninges and the cerebrospinal fluid (CSF)). The cytokines secreted by activated leukocytes residing at the borders were shown to affect neurotrophic factors production within the parenchyma. Here, we suggest that such a dialogue is stimulated at the brain's borders, upon need, by a "danger" signal that originates in the parenchyma in response to any destabilizing event, and discuss the potential role of reactive oxygen species (ROS) in transmitting this signal. Accordingly, a failure to restore balance is likely to lead to aberrant responses to subsequent events. This view thus supports the contention that circulating immune cells are required to maintain the brain's balanced activity and suggests a novel mechanism whereby the surveying immune cells are sensing the brain's status and needs.
Asunto(s)
Inmunidad Adaptativa/inmunología , Encéfalo/inmunología , Inmunidad Adaptativa/fisiología , Animales , Autoinmunidad/inmunología , Autoinmunidad/fisiología , Encéfalo/metabolismo , Homeostasis/inmunología , Homeostasis/fisiología , Humanos , Inmunidad Celular/inmunología , Inmunidad Celular/fisiología , Inflamación/inmunología , Inflamación/fisiopatología , Ratones , Plasticidad Neuronal/fisiología , Oxidación-Reducción , Transducción de Señal/fisiología , Linfocitos T/inmunología , Linfocitos T/fisiologíaRESUMEN
Amyotrophic lateral sclerosis (ALS) is a devastating disease, characterized by extremely rapid loss of motor neurons. Our studies over the last decade have established CD4(+) T cells as important players in central nervous system maintenance and repair. Those results, together with recent findings that CD4(+) T cells play a protective role in mouse models of ALS, led us to the current hypothesis that in ALS, a rapid T-cell malfunction may develop in parallel to the motor neuron dysfunction. Here, we tested this hypothesis by assessing thymic function, which serves as a measure of peripheral T-cell availability, in an animal model of ALS (mSOD1 [superoxide dismutase] mice; G93A) and in human patients. We found a significant reduction in thymic progenitor-cell content, and abnormal thymic histology in 3-4-month-old mSOD1 mice. In ALS patients, we found a decline in thymic output, manifested in the reduction in blood levels of T-cell receptor rearrangement excision circles, a non-invasive measure of thymic function, and demonstrated a restricted T-cell repertoire. The morbidity of the peripheral immune cells was also manifested in the increase of pro-apoptotic BAX/BCXL2 expression ratio in peripheral blood mononuclear cells (PBMCs) of these patients. In addition, gene expression screening in the same PBMCs, revealed in the ALS patients a reduction in key genes known to be associated with T-cell activity, including: CD80, CD86, IFNG and IL18. In light of the reported beneficial role of T cells in animal models of ALS, the present observation of thymic dysfunction, both in human patients and in an animal model, might be a co-pathological factor in ALS, regardless of the disease aetiology. These findings may lead to the development of novel therapeutic approaches directed at overcoming the thymic defect and T-cell deficiency.
Asunto(s)
Esclerosis Amiotrófica Lateral/inmunología , Esclerosis Amiotrófica Lateral/patología , Perfilación de la Expresión Génica , Timo/fisiopatología , Adulto , Animales , Linfocitos T CD4-Positivos/inmunología , Modelos Animales de Enfermedad , Femenino , Reordenamiento Génico de Linfocito T , Humanos , Masculino , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Timo/inmunologíaRESUMEN
T-cell-mediated autoimmunity participates in physiological defense, maintenance and repair of the adult brain. However, unless such autoimmune responses to insults are rigorously controlled, they might lead to an autoimmune disease or other immune-related defects, where destructive activity outweighs the beneficial effect. Here, we discuss these apparently contradictory effects of autoimmunity in schizophrenic patients, whose typical immune aberrations have prompted recent speculation about an autoimmune-related etiology. We found that, although schizophrenic patients have active immune systems, they often lack autoimmune clones specifically reactive to a major myelin protein, myelin basic protein (MBP). This, in conjunction with our discovery in rodents that T cells that recognize brain-resident proteins are needed for normal cognitive functioning, led us to propose an immune-based neurodevelopmental hypothesis, in which autoimmune-T-cell deficiency is suggested to cause onset or progression of schizophrenia.
Asunto(s)
Autoinmunidad , Esquizofrenia/inmunología , Linfocitos T/inmunología , Adolescente , Adulto , Animales , Humanos , Ratones , Proteína Básica de Mielina/inmunología , Esquizofrenia/etiología , Esquizofrenia/fisiopatologíaRESUMEN
Fighting off neuronal degeneration requires a well controlled T-cell response against self-antigens residing in sites of the CNS damage. The ability to evoke this response is normally suppressed by naturally occurring CD4+CD25+ regulatory T-cells (Treg). No physiological compound that controls Treg activity has yet been identified. Here, we show that dopamine, acting via type 1 dopamine receptors (found here to be preferentially expressed by Treg), reduces the suppressive activity and the adhesive and migratory abilities of Treg. Treg activity was correlated with activation of the ERK1/2 (extracellular signal-regulated kinase 1/2) signaling pathway. Systemic injection of dopamine or an agonist of its type 1 receptors significantly enhanced, via a T-cell-dependent mechanism, protection against neuronal death after CNS mechanical and biochemical injury. These findings shed light on the physiological mechanisms controlling Treg and might open the way to novel therapeutic strategies for downregulating Treg activity (e.g., in neuronal degeneration) or for strengthening it (in autoimmune diseases).
Asunto(s)
Linfocitos T CD4-Positivos/metabolismo , Dopamina/fisiología , Quinasas MAP Reguladas por Señal Extracelular/metabolismo , Degeneración Nerviosa/metabolismo , Traumatismos del Nervio Óptico/metabolismo , Receptores de Interleucina-2/metabolismo , Animales , Adhesión Celular/efectos de los fármacos , Movimiento Celular/efectos de los fármacos , Separación Celular , Supervivencia Celular/efectos de los fármacos , Células Cultivadas , Modelos Animales de Enfermedad , Dopamina/metabolismo , Dopamina/farmacología , Agonistas de Dopamina/farmacología , Regulación hacia Abajo/inmunología , Regulación hacia Abajo/fisiología , Inhibidores Enzimáticos/farmacología , Quinasas MAP Reguladas por Señal Extracelular/antagonistas & inhibidores , Ácido Glutámico , Tolerancia Inmunológica/efectos de los fármacos , Tolerancia Inmunológica/fisiología , Ratones , Compresión Nerviosa , Degeneración Nerviosa/tratamiento farmacológico , Degeneración Nerviosa/inmunología , Fármacos Neuroprotectores/farmacología , Nervio Óptico/metabolismo , Nervio Óptico/patología , Receptores de Dopamina D1/agonistas , Receptores de Dopamina D1/metabolismo , Receptores de Dopamina D5 , Células Ganglionares de la Retina/efectos de los fármacos , Células Ganglionares de la Retina/metabolismo , Células Ganglionares de la Retina/patología , Transducción de Señal/efectos de los fármacos , Transducción de Señal/fisiologíaRESUMEN
Peripheral cellular immunity was recently shown to play a critical role in brain plasticity and performance. The antigenic specificity of the participating T cells, however, was not investigated, and nor was their relevance to psychological stress. Here we show, using a mouse model, that adaptive immunity mitigates maladaptation to the acute psychological stress known to trigger abnormal behaviors reminiscent of human post-traumatic stress disorder. Assessment of behavioral adaptation (measured by the acoustic startle response and avoidance behavior) in mice after their exposure to predator odor revealed that maladaptation was several times more prevalent in T cell-deficient mice than in their wild-type counterparts. A single population of T cells reactive to central nervous system (CNS)-associated self-protein was sufficient to endow immune-deficient mice with the ability to withstand the psychological stress. Naturally occurring CD4+CD25+ regulatory T cells were found to suppress this endogenous anti-stress attribute. These findings suggest that T cells specific to abundantly expressed CNS antigens are responsible for brain tissue homeostasis and help the individual to cope with stressful life episodes. They might also point the way to development of immune-based therapies for mental disorders, based either on up-regulation of T cells that partially cross-react with self-antigens or on weakening of the activity of regulatory T cells.
Asunto(s)
Adaptación Fisiológica/inmunología , Linfocitos T CD4-Positivos/inmunología , Tolerancia Inmunológica/inmunología , Inmunidad Celular/inmunología , Subunidad alfa del Receptor de Interleucina-2/inmunología , Estrés Psicológico/inmunología , Adaptación Psicológica/fisiología , Animales , Autoinmunidad/inmunología , Sistema Nervioso Central/inmunología , Modelos Animales de Enfermedad , Regulación hacia Abajo/inmunología , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones SCID , Ratones Transgénicos , Proteína Básica de Mielina/inmunología , Proteínas del Tejido Nervioso/inmunología , Trastornos por Estrés Postraumático/inmunología , Trastornos por Estrés Postraumático/fisiopatología , Estrés Psicológico/fisiopatologíaRESUMEN
The effects of the adaptive immune system on the cognitive performance and abnormal behaviors seen in mental disorders such as schizophrenia have never been documented. Here, we show that mice deprived of mature T cells manifested cognitive deficits and behavioral abnormalities, which were remediable by T cell restoration. T cell-based vaccination, using glatiramer acetate (copolymer-1, a weak agonist of numerous self-reactive T cells), can overcome the behavioral and cognitive abnormalities that accompany neurotransmitter imbalance induced by (+)dizocilpine maleate (MK-801) or amphetamine. The results, by suggesting that peripheral T cell deficit can lead to cognitive and behavioral impairment, highlight the importance of properly functioning adaptive immunity in the maintenance of mental activity and in coping with conditions leading to cognitive deficits. These findings point to critical factors likely to contribute to age- and AIDS-related dementias and might herald the development of a therapeutic vaccination for fighting off cognitive dysfunction and psychiatric conditions.