Are microglial cells the regulators of lymphocyte responses in the CNS?

The infiltration of immune cells in the central nervous system is a common hallmark in different neuroinflammatory conditions. Accumulating evidence indicates that resident glial cells can establish a cross-talk with infiltrated immune cells, including T-cells, regulating their recruitment, activation and function within the CNS. Although the healthy CNS has been thought to be devoid of professional dendritic cells (DCs), numerous studies have reported the presence of a population of DCs in specific locations such as the meninges, choroid plexuses and the perivascular space. Moreover, the infiltration of DC precursors during neuroinflammatory situations has been proposed, suggesting a putative role of these cells in the regulation of lymphocyte activity within the CNS. On the other hand, under specific circumstances, microglial cells are able to acquire a phenotype of DC expressing a wide range of molecules that equip these cells with all the necessary machinery for communication with T-cells. In this review, we summarize the current knowledge on the expression of molecules involved in the cross-talk with T-cells in both microglial cells and DCs and discuss the potential contribution of each of these cell populations on the control of lymphocyte function within the CNS

Chronic IL-10 overproduction disrupts microglia-neuron dialogue similar to aging, resulting in impaired hippocampal neurogenesis and spatial memory

Altres ajuts: Acord transformatiu CRUE-CSICThis work was supported by the Spanish Ministry of Economy and Business (BFU2014-55459 and BFU2017-87843-R).The subgranular zone of the dentate gyrus is an adult neurogenic niche where new neurons are continuously generated. A dramatic hippocampal neurogenesis decline occurs with increasing age, contributing to cognitive deficits. The process of neurogenesis is intimately regulated by the microenvironment, with inflammation being considered a strong negative factor for this process. Thus, we hypothesize that the reduction of new neurons in the aged brain could be attributed to the age-related microenvironmental changes towards a pro-inflammatory status. In this work, we evaluated whether an anti-inflammatory microenvironment could counteract the negative effect of age on promoting new hippocampal neurons. Surprisingly, our results show that transgenic animals chronically overexpressing IL-10 by astrocytes present a decreased hippocampal neurogenesis in adulthood. This results from an impairment in the survival of neural newborn cells without differences in cell proliferation. In parallel, hippocampal-dependent spatial learning and memory processes were affected by IL-10 overproduction as assessed by the Morris water maze test. Microglial cells, which are key players in the neurogenesis process, presented a different phenotype in transgenic animals characterized by high activation together with alterations in receptors involved in neuronal communication, such as CD200R and CX3CR1. Interestingly, the changes described in adult transgenic animals were similar to those observed by the effect of normal aging. Thus, our data suggest that chronic IL-10 overproduction mimics the physiological age-related disruption of the microglia-neuron dialogue, resulting in hippocampal neurogenesis decrease and spatial memory impairment

Differential Roles of TREM2+ Microglia in Anterograde and Retrograde Axonal Injury Models

Microglia are the main immune cells of the central nervous system (CNS), and they are devoted to the active surveillance of the CNS during homeostasis and disease. In the last years, the microglial receptor Triggering Receptor Expressed on Myeloid cells-2 (TREM2) has been defined to mediate several microglial functions, including phagocytosis, survival, proliferation, and migration, and to be a key regulator of a new common microglial signature induced under neurodegenerative conditions and aging, also known as disease-associated microglia (DAM). Although microglial TREM2 has been mainly studied in chronic neurodegenerative diseases, few studies address its regulation and functions in acute inflammatory injuries. In this context, the present work aims to study the regulation of TREM2 and its functions after reparative axonal injuries, using two-well established animal models of anterograde and retrograde neuronal degeneration: the perforant pathway transection (PPT) and the facial nerve axotomy (FNA). Our results indicate the appearance of a subpopulation of microglia expressing TREM2 after both anterograde and retrograde axonal injury. TREM2+ microglia were not directly related to proliferation, instead, they were associated with specific recognition and/or phagocytosis of myelin and degenerating neurons, as assessed by immunohistochemistry and flow cytometry. Characterization of TREM2+ microglia showed expression of CD16/32, CD68, and occasional Galectin-3. However, specific singularities within each model were observed in P2RY12 expression, which was only downregulated after PPT, and in ApoE, where de novo expression was detected only in TREM2+ microglia after FNA. Finally, we report that the pro-inflammatory or anti-inflammatory cytokine microenvironment, which may affect phagocytosis, did not directly modify the induction of TREM2+ subpopulation in any injury model, although it changed TREM2 levels due to modification of the microglial activation pattern. In conclusion, we describe a unique TREM2+ microglial subpopulation induced after axonal injury, which is directly associated with phagocytosis of specific cell remnants and show different phenotypes, depending on the microglial activation status and the degree of tissue injury

From Mouse To Human : Comparative Analysis Between Grey And White Matter By Synchrotron-Fourier Transformed Infrared Microspectroscopy

Fourier Transform Infrared microspectroscopy (μFTIR) is a very useful method to analyze the biochemical properties of biological samples in situ. Many diseases affecting the central nervous system (CNS) have been studied using this method, to elucidate alterations in lipid oxidation or protein aggregation, among others. In this work, we describe in detail the characteristics between grey matter (GM) and white matter (WM) areas of the human brain by μFTIR, and we compare them with the mouse brain (strain C57BL/6), the most used animal model in neurological disorders. Our results show a clear different infrared profile between brain areas in the lipid region of both species. After applying a second derivative in the data, we established a 1.5 threshold value for the lipid/protein ratio to discriminate between GM and WM areas in non-pathological conditions. Furthermore, we demonstrated intrinsic differences of lipids and proteins by cerebral area. Lipids from GM present higher C=CH, C=O and CH3 functional groups compared to WM in humans and mice. Regarding proteins, GM present lower Amide II amounts and higher intramolecular β-sheet structure amounts with respect to WM in both species. However, the presence of intermolecular β-sheet structures, which is related to β-aggregation, was only observed in the GM of some human individuals. The present study defines the relevant biochemical properties of non-pathological human and mouse brains by μFTIR as a benchmark for future studies involving CNS pathological samples

TRPV2: A Key Player in Myelination Disorders of the Central Nervous System

Transient potential receptor vanilloid 2 (TRPV2) is widely expressed through the nervous system and specifically found in neuronal subpopulations and some glial cells. TRPV2 is known to be sensitized by methionine oxidation, which results from inflammation. Here we aim to characterize the expression and regulation of TRPV2 in myelination pathologies, such as hypomyelination and demyelination. We validated the interaction between TRPV2 and its putative interactor Opalin, an oligodendrocyte marker, in mixed glial cultures under pro- and anti-inflammatory conditions. Then, we characterized TRPV2 time-course expression in experimental animal models of hypomyelination (jimpy mice) and de-/remyelination (cuprizone intoxication and experimental autoimmune encephalomyelitis (EAE)). TRPV2 showed upregulation associated with remyelination, inflammation in cuprizone and EAE models, and downregulation in hypomyelinated jimpy mice. TRPV2 expression was altered in human samples of multiple sclerosis (MS) patients. Additionally, we analyzed the expression of methionine sulfoxide reductase A (MSRA), an enzyme that reduces oxidated methionines in TRPV2, which we found increased in inflammatory conditions. These results suggest that TRPV2 may be a key player in myelination in accordance with the recapitulation hypothesis, and that it may become an interesting clinical target in the treatment of demyelination disorders

TRPV2 : a Key Player in Myelination Disorders of the Central Nervous System

Transient potential receptor vanilloid 2 (TRPV2) is widely expressed through the nervous system and specifically found in neuronal subpopulations and some glial cells. TRPV2 is known to be sensitized by methionine oxidation, which results from inflammation. Here we aim to characterize the expression and regulation of TRPV2 in myelination pathologies, such as hypomyelination and demyelination. We validated the interaction between TRPV2 and its putative interactor Opalin, an oligodendrocyte marker, in mixed glial cultures under pro- and anti-inflammatory conditions. Then, we characterized TRPV2 time-course expression in experimental animal models of hypomyelination (jimpy mice) and de-/remyelination (cuprizone intoxication and experimental autoimmune encephalomyelitis (EAE)). TRPV2 showed upregulation associated with remyelination, inflammation in cuprizone and EAE models, and downregulation in hypomyelinated jimpy mice. TRPV2 expression was altered in human samples of multiple sclerosis (MS) patients. Additionally, we analyzed the expression of methionine sulfoxide reductase A (MSRA), an enzyme that reduces oxidated methionines in TRPV2, which we found increased in inflammatory conditions. These results suggest that TRPV2 may be a key player in myelination in accordance with the recapitulation hypothesis, and that it may become an interesting clinical target in the treatment of demyelination disorders

Papel de la microglía en la regulación de la respuesta inmunitaria adquirida

Numerosos estudios han demostrado a lo largo de los años, el papel fundamental que juegan las células de microglía en el funcionamiento del SNC. No sólo en condiciones normales, donde controlan la correcta homeóstasis del tejido, sino también en todas aquellas situaciones que, como consecuencia de alteraciones y procesos patológicos diversos, conllevan a una pérdida de esta homeóstasis. En respuesta a todas estas situaciones, las células de microglía son capaces de detectar rápidamente el daño y actuar de una manera específica en función del tipo de perturbación que se produzca en su entorno. Esta respuesta microglial ha sido ampliamente estudiada en daños agudos, en los que la microglía actúa como parte del sistema inmune innato, sin embargo los procesos que subyacen a la reactividad microglial ante una situación de inmunidad adquirida, así como la comunicación que se establece entre estas células microgliales y las células inmunes periféricas infiltradas permanecen en muchos aspectos sin esclarecer. En el presente trabajo hemos caracterizado el patrón de reactividad microglial y su relación con las diferentes poblaciones de linfocitos infiltrados a lo largo de las diferentes fases de la evolución que acontecen en un modelo agudo de encefalopatía autoinmune experimental (EAE). Nuestros estudios demuestran que las células de microglía se activan en respuesta a la inducción de la EAE y presentan un patrón de activación específico en cada una de las fases. Durante la fase de inducción y pico del proceso patológico, en estrecha relación con el aumento de la sintomatología clínica que se manifiesta por un progresivo deterioro de las funciones motoras, estas células microgliales experimentan cambios morfológicos y en su distribución acumulándose alrededor de los vasos sanguíneos. Además de microglía reactiva y posiblemente de macrófagos de origen sanguíneo, se observa también un gran número de linfocitos infiltrados, mayoritariamente del tipo T-cooperador y subtipo Th1 (pro-inflamatorio), si bien también se observan linfocitos T-citotóxicos y T-γδ. En estas fases, la activación microglial se caracteriza a nivel fenotípico por el aumento en la expresión de moléculas del complejo mayor de histocompatibilidad clase I y clase II (MHC-clase I y MHC-clase II) sin expresión concomitante de moléculas co-estimuladoras B7.1 o B7.2, es decir las células de microglía activadas presentan en estas circunstancias un fenotipo característico de células dendríticas inmaduras; hecho que hemos corroborado con la demostración de la expresión del marcador CD1. En este contexto, la señal que inducen estas células de microglía a los linfocitos infiltrados, podría estar implicada en la modulación del proceso inflamatorio induciendo la apoptosis o anergia linfocitaria. Durante la fase de recuperación, a pesar de que los animales experimentan una progresiva mejora sintomatológica, las células de microglía siguen mostrando una morfología, distribución y patrón de expresión de moléculas característicos de células reactivas. Si bien, en general, las células de microglía siguen mostrando el mismo patrón fenotípico (CD1+, MHC-I+, MHC-II+, B7.1- y B7.2-), aquellas localizadas en el entorno de algunos vasos sanguíneos expresan diferencialmente la molécula B7.2. Durante esta fase, además, el número total de linfocitos T-cooperadores, T-citotóxicos y T-γδ se mantiene muy elevado con valores similares a los observados en las fases anteriores. Es interesante señalar que ya no encontramos linfocitos Th1 y la población de T-cooperadores está constituida por los subtipos Th17 y T-regs. Los linfocitos que se acumulan en las inmediaciones de los vasos sanguíneos expresan CTLA-4, uno de los co-receptores de B7.2. En este nuevo contexto, la interacción de las células de microglía B7.2+ con estos linfocitos CTLA-4+ podría ser la responsable de la resolución de la respuesta immunitaria y la inducción de la tolerancia. En su conjunto los resultados obtenidos evidencian que la microglía juega un papel clave en la evolución de la respuesta inmune adquirida modulando la activación e inactivación de las diferentes poblaciones linfocitarias implicadas tanto en la inducción del proceso inmune/inflamatorio como en su posterior resolución. La realización de este trabajo ha sido financiada por las siguientes ayudas: Beca pre-doctoral de formación de investigadores de la UAB (UAB2004-11), Fundación La Maratón de TV3, Fundación Alicia Koplowitz, Fundación Uriach y Ministerio Español de Ciencia e Innovación (BFU2005-02783, BFU2008-04407).Over the years, numerous studies have demonstrated the fundamental role played by microglial cells in the CNS, not only in normal conditions where they control the correct tissue homeostasis, but also in all those situations in which, as a result of alterations and pathologies, homeostasis may be disturbed. Thus, when the integrity of the nervous tissue is disrupted, microglial cells are activated, showing specific activation patterns which fully depend on changes in the particular micro-environment. The microglial response has been widely studied in acute injuries in which microglia act as an intrinsic element of the innate immune system. However, the processes underlying microglial reactivity in situations of acquired immunity, as well as the relationship established between these microglial cells and infiltrating peripheral immune cells, remain poorly understood. In this study we have characterized the pattern of microglial reactivity and their relationship with the different populations of infiltrated lymphocytes, along the evolution of an acute model of experimental autoimmune encephalopathy (EAE) induced in Lewis rat. Our studies have demonstrated that microglial cells became activated in response to EAE induction, showing a specific activation pattern in each phase along disease evolution. During the inductive and peak phases, microglial cells showed changes in morphology and distribution, in close association with the increase of clinical symptoms, manifested by a progressive deterioration of motor function. These microglial cells progressively shorten their ramifications leading to amoeboid morphologies. Microglia and blood-borne macrophages increased in number and accumulated around blood vessels. In addition, a large number of infiltrated lymphocytes were also detected during the inductive and peak phases. These lymphocytes belong mostly to the T-helper phenotype (pro-inflammatory Th1 cells), although T-cytotoxic and γδ T-cells were also observed. Activated microglial cells displayed an immature dendritic cell phenotype characterized by expression of CD1 and major histocompatibility complexes class I and class II (MHC-class I and MHC-class II) without concomitant expression of B7.1 or B7.2 co-stimulatory molecules. In addition, these activated microglia expressed CD1, a marker of immature dendritic cells. In this context, the signal that these immature dendritic cell-like microglial cells induced to infiltrated lymphocytes may provoke lymphocyte apoptosis or anergy. During the recovery phase, animals experienced a gradual improvement in symptomatology, although microglial cells in this phase still showed a morphology, distribution and phenotype characteristics of reactive cells. In general, these microglial cells displayed the same immature dendritic cell phenotype (CD1+, MHC-I+, MHC-II+, B7.1- and B7.2-) observed during earlier phases. Noticeably, microglial cells located around blood vessels express B7.2. The total number of T-helper, T-cytotoxic and γδ T-cells remained very high with values close to those observed during the inductive and peak phases. Interestingly, we do not find Th1 lymphocytes during the recovery phase, and the population of T-helper cells mainly consists of Th17 and T-regs subtypes. Lymphocytes accumulated in the vicinity of blood vessels expressed CTLA-4, one of the B7.2 co¬receptors. In this new context, the interaction between B7.2+ microglial cells and CTLA-4+ lymphocytes could be responsible for the immune response resolution and the induction of subsequent tolerance. Altogether, these results show that microglia play a key role in the evolution of the acquired immune response, modulating the activation and inactivation of the different lymphocyte populations involved in both the induction of the immune/inflammatory process and its subsequent resolution. This work was supported by: UAB Pre-doctoral fellow (UAB2004-11), Fundación La Maratón de TV3, Fundación Alicia Koplowitz, Fundación Uriach y Ministerio Español de Ciencia e Innovación (BFU2005-02783, BFU2008-04407)

Are microglial cells the regulators of lymphocyte responses in the CNS?

The infiltration of immune cells in the central nervous system is a common hallmark in different neuroinflammatory conditions. Accumulating evidence indicates that resident glial cells can establish a cross-talk with infiltrated immune cells, including T-cells, regulating their recruitment, activation and function within the CNS. Although the healthy CNS has been thought to be devoid of professional dendritic cells (DCs), numerous studies have reported the presence of a population of DCs in specific locations such as the meninges, choroid plexuses and the perivascular space. Moreover, the infiltration of DC precursors during neuroinflammatory situations has been proposed, suggesting a putative role of these cells in the regulation of lymphocyte activity within the CNS. On the other hand, under specific circumstances, microglial cells are able to acquire a phenotype of DC expressing a wide range of molecules that equip these cells with all the necessary machinery for communication with T-cells. In this review, we summarize the current knowledge on the expression of molecules involved in the cross-talk with T-cells in both microglial cells and DCs and discuss the potential contribution of each of these cell populations on the control of lymphocyte function within the CNS

Papel de la microglía en la regulación de la respuesta inmunitaria adquirida

Descripció del recurs: el 14 de febrer de 2011Numerosos estudios han demostrado a lo largo de los años, el papel fundamental que juegan las células de microglía en el funcionamiento del SNC. No sólo en condiciones normales, donde controlan la correcta homeóstasis del tejido, sino también en todas aquellas situaciones que, como consecuencia de alteraciones y procesos patológicos diversos, conllevan a una pérdida de esta homeóstasis. En respuesta a todas estas situaciones, las células de microglía son capaces de detectar rápidamente el daño y actuar de una manera específica en función del tipo de perturbación que se produzca en su entorno. Esta respuesta microglial ha sido ampliamente estudiada en daños agudos, en los que la microglía actúa como parte del sistema inmune innato, sin embargo los procesos que subyacen a la reactividad microglial ante una situación de inmunidad adquirida, así como la comunicación que se establece entre estas células microgliales y las células inmunes periféricas infiltradas permanecen en muchos aspectos sin esclarecer. En el presente trabajo hemos caracterizado el patrón de reactividad microglial y su relación con las diferentes poblaciones de linfocitos infiltrados a lo largo de las diferentes fases de la evolución que acontecen en un modelo agudo de encefalopatía autoinmune experimental (EAE). Nuestros estudios demuestran que las células de microglía se activan en respuesta a la inducción de la EAE y presentan un patrón de activación específico en cada una de las fases. Durante la fase de inducción y pico del proceso patológico, en estrecha relación con el aumento de la sintomatología clínica que se manifiesta por un progresivo deterioro de las funciones motoras, estas células microgliales experimentan cambios morfológicos y en su distribución acumulándose alrededor de los vasos sanguíneos. Además de microglía reactiva y posiblemente de macrófagos de origen sanguíneo, se observa también un gran número de linfocitos infiltrados, mayoritariamente del tipo T-cooperador y subtipo Th1 (pro-inflamatorio), si bien también se observan linfocitos T-citotóxicos y T-γδ. En estas fases, la activación microglial se caracteriza a nivel fenotípico por el aumento en la expresión de moléculas del complejo mayor de histocompatibilidad clase I y clase II (MHC-clase I y MHC-clase II) sin expresión concomitante de moléculas co-estimuladoras B7.1 o B7.2, es decir las células de microglía activadas presentan en estas circunstancias un fenotipo característico de células dendríticas inmaduras; hecho que hemos corroborado con la demostración de la expresión del marcador CD1. En este contexto, la señal que inducen estas células de microglía a los linfocitos infiltrados, podría estar implicada en la modulación del proceso inflamatorio induciendo la apoptosis o anergia linfocitaria. Durante la fase de recuperación, a pesar de que los animales experimentan una progresiva mejora sintomatológica, las células de microglía siguen mostrando una morfología, distribución y patrón de expresión de moléculas característicos de células reactivas. Si bien, en general, las células de microglía siguen mostrando el mismo patrón fenotípico (CD1+, MHC-I+, MHC-II+, B7.1- y B7.2-), aquellas localizadas en el entorno de algunos vasos sanguíneos expresan diferencialmente la molécula B7.2. Durante esta fase, además, el número total de linfocitos T-cooperadores, T-citotóxicos y T-γδ se mantiene muy elevado con valores similares a los observados en las fases anteriores. Es interesante señalar que ya no encontramos linfocitos Th1 y la población de T-cooperadores está constituida por los subtipos Th17 y T-regs. Los linfocitos que se acumulan en las inmediaciones de los vasos sanguíneos expresan CTLA-4, uno de los co-receptores de B7.2. En este nuevo contexto, la interacción de las células de microglía B7.2+ con estos linfocitos CTLA-4+ podría ser la responsable de la resolución de la respuesta immunitaria y la inducción de la tolerancia. En su conjunto los resultados obtenidos evidencian que la microglía juega un papel clave en la evolución de la respuesta inmune adquirida modulando la activación e inactivación de las diferentes poblaciones linfocitarias implicadas tanto en la inducción del proceso inmune/inflamatorio como en su posterior resolución. La realización de este trabajo ha sido financiada por las siguientes ayudas: Beca pre-doctoral de formación de investigadores de la UAB (UAB2004-11), Fundación La Maratón de TV3, Fundación Alicia Koplowitz, Fundación Uriach y Ministerio Español de Ciencia e Innovación (BFU2005-02783, BFU2008-04407).Over the years, numerous studies have demonstrated the fundamental role played by microglial cells in the CNS, not only in normal conditions where they control the correct tissue homeostasis, but also in all those situations in which, as a result of alterations and pathologies, homeostasis may be disturbed. Thus, when the integrity of the nervous tissue is disrupted, microglial cells are activated, showing specific activation patterns which fully depend on changes in the particular micro-environment. The microglial response has been widely studied in acute injuries in which microglia act as an intrinsic element of the innate immune system. However, the processes underlying microglial reactivity in situations of acquired immunity, as well as the relationship established between these microglial cells and infiltrating peripheral immune cells, remain poorly understood. In this study we have characterized the pattern of microglial reactivity and their relationship with the different populations of infiltrated lymphocytes, along the evolution of an acute model of experimental autoimmune encephalopathy (EAE) induced in Lewis rat. Our studies have demonstrated that microglial cells became activated in response to EAE induction, showing a specific activation pattern in each phase along disease evolution. During the inductive and peak phases, microglial cells showed changes in morphology and distribution, in close association with the increase of clinical symptoms, manifested by a progressive deterioration of motor function. These microglial cells progressively shorten their ramifications leading to amoeboid morphologies. Microglia and blood-borne macrophages increased in number and accumulated around blood vessels. In addition, a large number of infiltrated lymphocytes were also detected during the inductive and peak phases. These lymphocytes belong mostly to the T-helper phenotype (pro-inflammatory Th1 cells), although T-cytotoxic and γδ T-cells were also observed. Activated microglial cells displayed an immature dendritic cell phenotype characterized by expression of CD1 and major histocompatibility complexes class I and class II (MHC-class I and MHC-class II) without concomitant expression of B7.1 or B7.2 co-stimulatory molecules. In addition, these activated microglia expressed CD1, a marker of immature dendritic cells. In this context, the signal that these immature dendritic cell-like microglial cells induced to infiltrated lymphocytes may provoke lymphocyte apoptosis or anergy. During the recovery phase, animals experienced a gradual improvement in symptomatology, although microglial cells in this phase still showed a morphology, distribution and phenotype characteristics of reactive cells. In general, these microglial cells displayed the same immature dendritic cell phenotype (CD1+, MHC-I+, MHC-II+, B7.1- and B7.2-) observed during earlier phases. Noticeably, microglial cells located around blood vessels express B7.2. The total number of T-helper, T-cytotoxic and γδ T-cells remained very high with values close to those observed during the inductive and peak phases. Interestingly, we do not find Th1 lymphocytes during the recovery phase, and the population of T-helper cells mainly consists of Th17 and T-regs subtypes. Lymphocytes accumulated in the vicinity of blood vessels expressed CTLA-4, one of the B7.2 co¬receptors. In this new context, the interaction between B7.2+ microglial cells and CTLA-4+ lymphocytes could be responsible for the immune response resolution and the induction of subsequent tolerance. Altogether, these results show that microglia play a key role in the evolution of the acquired immune response, modulating the activation and inactivation of the different lymphocyte populations involved in both the induction of the immune/inflammatory process and its subsequent resolution. This work was supported by: UAB Pre-doctoral fellow (UAB2004-11), Fundación La Maratón de TV3, Fundación Alicia Koplowitz, Fundación Uriach y Ministerio Español de Ciencia e Innovación (BFU2005-02783, BFU2008-04407)

Increase in Th17 and T-reg lymphocytes and decrease of IL22 correlate with the recovery phase of acute EAE IN rat

Experimental autoimmune encephalomyelitis (EAE), a well-established model of multiple sclerosis, is characterised by microglial activation and lymphocyte infiltration. Induction of EAE in Lewis rats produces an acute monophasic disease characterised by a single peak of disability followed by a spontaneous and complete recovery and a subsequent tolerance to further immunizations. In the current study we have performed a detailed analysis of the dynamics of different lymphocyte populations and cytokine profile along the induction, peak, recovery and post-recovery phases in this paradigm. MBP-injected rats were sacrificed attending exclusively to their clinical score, and the different populations of T-lymphocytes as well as the dynamics of different pro- and anti-inflammatory cytokines were analysed in the spinal cord by flow cytometry, immunohistochemistry and ELISA. Our results revealed that, during the induction and peak phases, in parallel to an increase in symptomatology, the number of CD3+ and CD4+ cells increased progressively, showing a Th1 phenotype, but unexpectedly during recovery, although clinical signs progressively decreased, the number and proportion of CD3+ and CD4+ populations remained unaltered. Interestingly, during this recovery phase, we observed a marked decrease of Th1 and an important increase in Th17 and T-reg cells. Moreover, our results indicate a specific cytokine expression profile along the EAE course characterized by no changes of IL10 and IL17 levels, decrease of IL21 on the peak, and high IL22 levels during the induction and peak phases that markedly decrease during recovery. In summary, these results revealed the existence of a specific pattern of lymphocyte infiltration and cytokine secretion along the different phases of the acute EAE model in Lewis rat that differs from those already described in chronic or relapsing-remitting mouse models, where Th17-cells were found mostly during the peak, suggesting a specific role of these lymphocytes and cytokines in the evolution of this acute EAE model