RESUMEN
Eomesodermin-expressing (Eomes+) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes+ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes+ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes+ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes+ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.
Asunto(s)
Enfermedades Neurodegenerativas , Proteínas de Dominio T Box , Linfocitos T Colaboradores-Inductores , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Masculino , Persona de Mediana Edad , Enfermedad de Alzheimer/inmunología , Enfermedad de Alzheimer/patología , Enfermedad de Alzheimer/metabolismo , Esclerosis Amiotrófica Lateral/inmunología , Granzimas/metabolismo , Enfermedades Neurodegenerativas/inmunología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Colaboradores-Inductores/inmunologíaRESUMEN
Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell-mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4+ T cells expressing Eomes (Eomes+ Th cells) in SPMS pathogenesis-a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes+ Th cells circulate in RRMS patient peripheral blood (n = 44), primary progressive MS (PPMS) patients (n = 25), or healthy controls (n = 42), but Eomes+ Th cells were significantly increased in SPMS (n = 105, P < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4+ T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes+ Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases (P < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.
Asunto(s)
Esclerosis Múltiple Crónica Progresiva/patología , Proteínas de Dominio T Box/metabolismo , Linfocitos T Colaboradores-Inductores/metabolismo , Adulto , Anciano , Biomarcadores/sangre , Encéfalo/patología , Progresión de la Enfermedad , Femenino , Granzimas/metabolismo , Humanos , Inflamación , Masculino , Persona de Mediana Edad , Esclerosis Múltiple Crónica Progresiva/sangre , Esclerosis Múltiple Crónica Progresiva/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/sangre , Esclerosis Múltiple Recurrente-Remitente/tratamiento farmacológico , Esclerosis Múltiple Recurrente-Remitente/patología , Adulto JovenRESUMEN
Induction of eomesodermin-positive CD4+ T cells (Eomes+ T helper [Th] cells) has recently been correlated with the transition from an acute stage to a later stage of experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis. Moreover, these cells' pathogenic role has been experimentally proven in EAE. While exploring how the pathogenic Eomes+ Th cells are generated during the course of EAE, we unexpectedly found that B cells and MHC class II+ myeloid cells isolated from the late EAE lesions strikingly up-regulated the expression of prolactin (PRL). We demonstrate that such PRL-producing cells have a unique potential to induce Eomes+ Th cells from naïve T cells ex vivo, and that anti-MHC class II antibody could block this process. Furthermore, PRL levels in the cerebrospinal fluid were significantly increased in the late phase of EAE, and blocking the production of PRL by bromocriptine or Zbtb20-specific siRNA significantly reduced the numbers of Eomes+ Th cells in the central nervous system (CNS) and ameliorated clinical signs in the later phase of EAE. The PRL dependency of Eomes+ Th cells was confirmed in a series of in vitro and ex vivo experiments. Collectively, these results indicate that extrapituitary PRL plays a crucial role in the CNS inflammation mediated by pathogenic Eomes+ Th cells. Cellular interactions involving PRL-producing immune cells could be considered as a therapeutic target for the prevention of chronic neuroinflammation.
Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Sistema Nervioso Central/inmunología , Inflamación/inmunología , Prolactina/inmunología , Proteínas de Dominio T Box/inmunología , Animales , Linfocitos B/inmunología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/inmunología , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/inmunología , Células Mieloides/inmunologíaRESUMEN
Experimental autoimmune uveoretinitis is an autoimmune disease induced in mice, which involves the infiltration of CD11b(+) macrophages and CD4(+) T cells into the normally immune-privileged retina. Damage is produced in the target organ following the activation of Th1 and Th17 T cells and by the release of cytotoxic mediators such as NO by activated macrophages. The majority of immune cells infiltrating into the retina are CD11b(+) myeloid cells, but, despite the presence of these APCs, relatively limited numbers of T cells are observed in the retina during the disease course. These T cells do not proliferate when leukocytes are isolated from the retina and restimulated in vitro, although they do produce both IFN-gamma and IL-17. T cell proliferation was restored by depleting the myeloid cells from the cultures and furthermore those isolated myeloid cells were able to regulate the proliferation of other T cells. The ability of macrophages to regulate proliferation depends on activation by T cell-produced IFN-gamma and autocrine TNF-alpha signaling in the myeloid cells via TNFR1. In the absence of TNFR1 signaling, relative T cell expansion in the retina is increased, indicating that regulatory myeloid cells may also act in vivo. However, TNFR1 signaling is also required for macrophages, but not T cells, to migrate into the target organ. Thus, in TNFR1 knock out mice, the amplification of autoimmunity is limited, leading to resistance to experimental autoimmune uveoretinitis induction.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Enfermedades Autoinmunes/patología , Células Mieloides/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/fisiología , Retinitis/inmunología , Retinitis/patología , Uveítis/inmunología , Uveítis/patología , Secuencia de Aminoácidos , Animales , Enfermedades Autoinmunes/genética , Movimiento Celular/genética , Movimiento Celular/inmunología , Células Cultivadas , Femenino , Macrófagos/inmunología , Macrófagos/metabolismo , Macrófagos/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Datos de Secuencia Molecular , Células Mieloides/metabolismo , Células Mieloides/patología , Receptores Tipo I de Factores de Necrosis Tumoral/deficiencia , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Retinitis/genética , Subgrupos de Linfocitos T/inmunología , Subgrupos de Linfocitos T/metabolismo , Subgrupos de Linfocitos T/patología , Receptores Señuelo del Factor de Necrosis Tumoral/deficiencia , Receptores Señuelo del Factor de Necrosis Tumoral/genética , Receptores Señuelo del Factor de Necrosis Tumoral/fisiología , Uveítis/genéticaRESUMEN
Macrophages (MÏ) are professional antigen-presenting cells, but when they accumulate at sites of inflammation, they can inhibit T-cell proliferation. In experimental autoimmune uveoretinitis, this limits the expansion of T cells within the target organ. To define requirements for the elaboration of this outcome, we have generated populations of MÏ in vitro that could also regulate T-cell responses; stimulating CD4(+) T-cell activation and cytokine production, but simultaneously suppressing T-cell proliferation. When T cells are removed from the influence of such cells, normal T-cell responses are restored. We show that tumour necrosis factor 1 (TNFR1) signalling is a critical checkpoint in the development of such MÏ, as TNFR1(-/-) MÏ are unable to suppress T-cell proliferation. This deficit in antigen-presenting cells results in a lack of production of prostaglandin E(2) (PGE(2)) and nitric oxide, which are critical effector mechanisms that inhibit T-cell division. However, TNFR1 signalling is not required for the inhibitory function of MÏ because we could circumvent the requirement for this receptor, by maturing MÏ in the presence of exogenous interferon-γ and PGE(2). This produced TNFR1(-/-) MÏ that inhibited T-cell proliferation and indicates that TNFR1 delivers a signal that is necessary for the development but not the execution of this function.
Asunto(s)
Macrófagos/inmunología , Receptores Tipo I de Factores de Necrosis Tumoral/metabolismo , Linfocitos T/metabolismo , Animales , Comunicación Celular , Diferenciación Celular/inmunología , Proliferación Celular , Células Cultivadas , Dinoprostona/genética , Dinoprostona/inmunología , Dinoprostona/metabolismo , Tolerancia Inmunológica , Interferón gamma/genética , Interferón gamma/inmunología , Interferón gamma/metabolismo , Macrófagos/citología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Receptores Tipo I de Factores de Necrosis Tumoral/genética , Transducción de Señal/genética , Transducción de Señal/inmunología , Linfocitos T/inmunología , Linfocitos T/patologíaRESUMEN
In chronic inflammation, across a number of quite different pathological conditions, monocytes accumulate. In autoimmune disease, these cells are widely recognised to play an inflammatory and tissue destructive role. But these cells also inhibit T cell proliferation by a range of different mechanisms that are accompanied by the depletion of specific amino acids in the local microenvironment and the downregulation of the T cell receptor zeta chain. This occurs within the pro-inflammatory environment and in the presence of Th1 (IFNgamma) and Th17 (IL-17) cytokines. In tumours, related cells are part of a population called myeloid-derived suppressor cells (MDSC) and they are associated with immunosuppression. Their depletion can lead to clinical improvement. In organ specific autoimmune disease, where such cells can be found in the spleen and in target organs, recent evidence indicates that they may play a role in limiting the T cell response to autoantigens in the target tissue. This occurs by a targeted disruption of T cell division. In this review we discuss evidence for the presence on MDSC in murine and human autoimmune disease and the mechanisms by which such cells inhibit T cell proliferation.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Tolerancia Inmunológica , Monocitos/inmunología , Animales , Arginasa/inmunología , Enfermedades Autoinmunes/sangre , Proliferación Celular , Enfermedad Crónica , Humanos , Inflamación/inmunología , Ratones , Mielopoyesis/inmunología , Óxido Nítrico Sintasa de Tipo II/inmunología , Especies Reactivas de Oxígeno/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/inmunología , Receptores de Antígenos de Linfocitos T gamma-delta/metabolismo , Receptores de Quimiocina/inmunología , Linfocitos T/inmunologíaRESUMEN
Development of acute experimental autoimmune encephalomyelitis (EAE) depends on Th17 cells expressing the nuclear factor NR4A2. However, in mice lacking NR4A2 in T cells, a late-onset disease is still inducible, despite a great reduction in acute inflammation. We here reveal that development of this late onset disease depends on cytotoxic T-cell-like CD4(+) T cells expressing the T-box transcription factor Eomesodermin (Eomes). T-cell-specific deletion of the Eomes gene remarkably ameliorates the late-onset EAE. Strikingly, similar Eomes(+) CD4(+) T cells are increased in the peripheral blood and cerebrospinal fluid from patients in a progressive state of multiple sclerosis. Collective data indicate an involvement of granzyme B and protease-activated receptor-1 in the neuroinflammation mediated by Eomes(+) CD4(+) T cells.
Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Granzimas/inmunología , Esclerosis Múltiple Crónica Progresiva/inmunología , Receptor PAR-1/inmunología , Proteínas de Dominio T Box/inmunología , Células Th17/inmunología , Adulto , Animales , Encefalomielitis Autoinmune Experimental/genética , Femenino , Humanos , Masculino , Ratones , Persona de Mediana Edad , Esclerosis Múltiple Recurrente-Remitente/inmunología , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/inmunología , Proteínas de Dominio T Box/genética , Linfocitos T Colaboradores-Inductores/inmunología , Adulto JovenRESUMEN
IL-17-producing CD4(+) T helper 17 (Th17) cells are pathogenic in a range of human autoimmune diseases and corresponding animal models. We now demonstrate that such T cells infiltrating the target organ during the induction of experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveoretinitis (EAU) specifically express NR4A2. Further, we reveal a critical involvement of NR4A2 in Th17 cell functions and Th17 cell-driven autoimmune diseases. When NR4A2 expression was blocked with siRNA, full Th17 differentiation was prevented in vitro: although cells expressed the master Th17 regulator, RORγt, they expressed reduced levels of IL-23R and were unable to produce IL-17 and IL-21. Notably, Th17 differentiation in the absence of NR4A2 was restored by exogenous IL-21, indicating that NR4A2 controls full maturation of Th17 cells via autocrine IL-21 signalling. Preventing NR4A2 expression in vivo by systemic treatment with NR4A2-specific siRNA also reduced Th17 effector responses and furthermore protected mice from EAE induction. In addition, the lack of disease was associated with a reduction in autocrine IL-21 production and IL-23R expression. Similar modulation of NR4A2 expression was also effective as an intervention, reversing established autoimmune responses and ameliorating clinical disease symptoms. Thus, NR4A2 appears to control Th17 differentiation and so plays an essential role in the development of Th17-mediated autoimmune disease. As NR4A2 is also upregulated during human autoimmune disease, targeting NR4A2 may provide a new therapeutic approach in treating autoimmune disease.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Encefalomielitis Autoinmune Experimental/metabolismo , Interleucinas/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/metabolismo , Animales , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/metabolismo , Autoinmunidad/genética , Autoinmunidad/inmunología , Diferenciación Celular/inmunología , Encefalomielitis Autoinmune Experimental/inducido químicamente , Encefalomielitis Autoinmune Experimental/inmunología , Regulación de la Expresión Génica , Humanos , Inflamación/inmunología , Inflamación/patología , Interleucinas/administración & dosificación , Interleucinas/genética , Ratones , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Miembro 2 del Grupo A de la Subfamilia 4 de Receptores Nucleares/genética , Transducción de Señal , Linfocitos T Colaboradores-Inductores/citología , Linfocitos T Colaboradores-Inductores/inmunología , Células Th17/inmunología , Células Th17/metabolismoRESUMEN
Experimental autoimmune uveoretinitis (EAU) is an animal model for human intraocular inflammatory disease. EAU is induced in B10.RIII mice by immunization with RBP-3 161-180 peptide and intraperitoneal pertussis toxin and is mediated by CD4(+) T cells that generate a clinically monophasic disease peaking approximately 2 weeks post-immunization. Collagenase digestion of retinal tissue allowed the quantification and characterization of leukocytes in the inflamed retina during disease progression. Using this method we identified three stages of disease. Initially there is a prodromal phase where we found significant changes in the number of leukocytes in the eye as early as 5 days post-immunization. This effect was, in part, non-antigen specific as a small increase in retinal leukocytes was also observed following immunization with OVA peptide. Following the prodrome there is a primary peak of infiltration including both CD4(+) T cells and CD11b(+) cells. This coincides with an early influx of neutrophils and is associated with a peak in IL-17-producing T cells. The neutrophils in the eye are CD11b(+) and Gr1(+) but can be distinguished from other myeloid cells by their high expression of Ly6G. The remaining CD11b(+)Gr1(+) cells can suppress proliferation and are analogous to myeloid derived suppressor cells which are found in tumors. The inflamed eye also contains a considerable proportion of FoxP3(+) regulatory cells. Following peak disease, the retina does not return to its pre-disease phenotype. Instead, fluctuations in infiltrating leukocyte numbers and changes to their relative composition continue, indicating that clinical recovery does not equate to the restoration of a normal retinal leukocyte population.
Asunto(s)
Enfermedades Autoinmunes/patología , Linfocitos T CD4-Positivos/inmunología , Retina/patología , Retinitis/patología , Uveítis/patología , Animales , Antígenos Ly/inmunología , Antígenos Ly/metabolismo , Enfermedades Autoinmunes/inmunología , Modelos Animales de Enfermedad , Proteínas del Ojo/inmunología , Humanos , Interleucina-17/inmunología , Ratones , Células Mieloides/inmunología , Neutrófilos/inmunología , Toxina del Pertussis/farmacología , Retina/inmunología , Retinitis/inmunología , Proteínas de Unión al Retinol/inmunología , Uveítis/inmunologíaRESUMEN
OBJECTIVE: To examine the efficacy of the immunomodulatory drug fingolimod (FTY720) as a rescue therapy for noninfectious intraocular inflammation. METHODS: Experimental autoimmune uveoretinitis, the murine correlate of human uveitis, was induced in B10.RIII mice. The mice were treated with 2 oral doses of fingolimod daily, either during early ocular infiltration or following clinical onset of the disease. At subsequent times, retinal infiltrates were examined and enumerated using flow cytometry, and structural disease was assessed and scored using histology. RESULTS: Fingolimod treatment, administered 2 days before disease onset, prevented inflammatory cells from infiltrating the retina, with corroborative suppression of histologic disease. A single dose of fingolimod was sufficient in clearing infiltrating leukocytes from the retina within 2 hours of treatment. Furthermore, a single dose of fingolimod administered after disease onset not only abolished retinal infiltrates but also prevented disease relapse for at least 3 weeks. CONCLUSIONS: A short-term, high-dose treatment with fingolimod rapidly reduces ocular infiltrates in experimental autoimmune uveoretinitis, leading to a normal myeloid cell count within the retina. When given at the early stages of intraocular inflammation, fingolimod resolves disease. Clinical Relevance This study directly demonstrates the therapeutic potential of fingolimod and an acute rescue intervention for human noninfectious posterior-segment intraocular inflammatory disease.
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Enfermedades Autoinmunes/tratamiento farmacológico , Inmunosupresores/administración & dosificación , Glicoles de Propileno/administración & dosificación , Retinitis/tratamiento farmacológico , Esfingosina/análogos & derivados , Uveítis/tratamiento farmacológico , Administración Oral , Animales , Enfermedades Autoinmunes/diagnóstico , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Esquema de Medicación , Tratamiento de Urgencia/métodos , Femenino , Clorhidrato de Fingolimod , Inmunohistoquímica , Ratones , Ratones Endogámicos BALB C , Distribución Aleatoria , Valores de Referencia , Retinitis/inmunología , Retinitis/patología , Sensibilidad y Especificidad , Esfingosina/administración & dosificación , Resultado del Tratamiento , Uveítis/inmunología , Uveítis/patologíaRESUMEN
PURPOSE: EAU is an established preclinical model for assessment of immunotherapeutic efficacy toward translation of therapy for posterior uveitis. Reliable screening of clinical features that correlate with underlying retinal changes and damage has not been possible to date. This study was undertaken to describe, validate, and correlate topical endoscopic fundus imaging (TEFI) with histologic features of murine experimental autoimmune uveoretinitis (EAU), with the intent of generating a rapid noninvasive panretinal assessment of ocular inflammation. METHODS: EAU was induced in B10.RIII mice by immunization with the peptide RBP-3(161-180). The clinical disease course (days 0-63) was monitored and documented using TEFI. Disease severity and pathology were confirmed at various time points by histologic assessment. The composition of the cell infiltrate was also examined and enumerated by flow cytometry. RESULTS: TEFI demonstrated the hallmark features of EAU, paralleling many of the clinical features of human uveitis, and closely aligned with underlying histologic changes, the severity of which correlated significantly with the number of infiltrating retinal leukocytes. Leukocytic infiltration occurred before manifestation of clinical disease and clinically fulminant disease, as well as cell infiltrate, resolved faster than histologic scores. During the resolution phase, neither the clinical appearance nor number of infiltrating retinal leukocytes returned to predisease levels. CONCLUSIONS: In EAU, there is a strong correlation between histologic severity and the number of infiltrating leukocytes into the retina. TEFI enhances the monitoring of clinical disease in a rapid and noninvasive fashion. Full assessment of preclinical immunotherapeutic efficacy requires the use of all three parameters: TEFI, histologic assessment, and flow cytometric analysis of retinal infiltrate.
Asunto(s)
Enfermedades Autoinmunes/diagnóstico , Diagnóstico por Imagen/métodos , Modelos Animales de Enfermedad , Fondo de Ojo , Retinitis/diagnóstico , Uveítis Posterior/diagnóstico , Animales , Antígenos CD/análisis , Enfermedades Autoinmunes/inducido químicamente , Enfermedades Autoinmunes/inmunología , Endoscopía , Proteínas del Ojo , Femenino , Citometría de Flujo , Leucocitos/inmunología , Ratones , Fragmentos de Péptidos , Fotograbar/métodos , Retinitis/inducido químicamente , Retinitis/inmunología , Proteínas de Unión al Retinol , Factores de Tiempo , Uveítis Posterior/inducido químicamente , Uveítis Posterior/inmunologíaRESUMEN
PURPOSE: To investigate the efficacy of the B subunit of Escherichia coli heat-labile enterotoxin (EtxB) in the treatment of ocular autoimmune disease. Murine experimental autoimmune uveoretinitis (EAU) is an animal model of autoimmune posterior uveitis initiated by retinal antigen-specific Th1 and Th17 CD4(+) T cells, which activate myeloid cells, inducing retinal damage. EtxB is a potent immune modulator that ameliorates other Th1-mediated autoimmune diseases, enhancing regulatory T-cell activity. METHODS: EAU was induced in B10.RIII mice by immunization with peptide hIRBP(161-180). Disease severity was measured by clinical and histologic assessment, and functional responses of macrophages (Mphis) and T cells were assessed, both in vivo and in cocultures in vitro. EtxB was administered intranasally daily for 4 days, starting either 3 days before or 3 days after EAU induction. RESULTS: Preimmunization treatment with EtxB protected mice from EAU, limiting both the number and the activation status of retinal infiltrating immune cells. Treatment after EAU induction did not alter the disease course, despite suppression of IFN-gamma. Although EtxB treatment of in vitro cocultures of T cells and Mphis increased IL-10 production, EtxB treatment in vivo increased the proportion and number of IL-17-producing CD4(+) cells infiltrating the eye. CONCLUSIONS: EtxB preimmunization protects mice from EAU induction by inhibiting Th1 responses, but the resultant reduction in IFN-gamma responses by EtxB does not effect infiltration or structural damage in established EAU, where Th17 responses predominate. These data highlight the critical importance of the dynamics of T-cell phenotype and infiltration during EAU when considering immunomodulatory therapy.
Asunto(s)
Enfermedades Autoinmunes/inmunología , Toxinas Bacterianas/inmunología , Enterotoxinas/inmunología , Proteínas de Escherichia coli/inmunología , Ovalbúmina/farmacología , Fragmentos de Péptidos/farmacología , Retinitis/inmunología , Proteínas de Unión al Retinol/farmacología , Linfocitos T Colaboradores-Inductores/inmunología , Células TH1/inmunología , Uveítis/inmunología , Secuencia de Aminoácidos , Animales , Células de la Médula Ósea/citología , Células de la Médula Ósea/inmunología , División Celular , Modelos Animales de Enfermedad , Macrófagos/citología , Macrófagos/inmunología , Ratones , Ratones Endogámicos C57BL , Ovalbúmina/química , Linfocitos T/inmunologíaRESUMEN
It is acknowledged that T cell interactions with mature dendritic cells (DC) lead to immunity, whereas interactions with immature DC lead to tolerance induction. Using a transgenic murine system, we have examined how DC expressing self-peptides control naive, self-reactive CD8+ T cell responses in vitro and in vivo. We have shown, for the first time, that immature DC can also stimulate productive activation of naive self-specific CD8+ T cells, which results in extensive proliferation, the expression of a highly activated cell surface phenotype, and differentiation into autoimmune CTL. Conversely, mature DC can induce abortive activation of naive CD8+ T cells, which is characterized by low-level proliferation, the expression of a partially activated cell surface phenotype which does not result in autoimmune CTL. Critically, both CD8+ T cell responses are determined by a combination of signals mediated by the DC, and that altering any one of these signals dramatically shifts the balance between autoimmunity and self-tolerance induction. We hypothesize that DC maintain the steady state of self-tolerance among self-specific CD8+ T cells in an active and dynamic manner, licensing productive immune responses against self-tissues only when required.
Asunto(s)
Autoinmunidad , Linfocitos T CD8-positivos/inmunología , Células Dendríticas/inmunología , Autotolerancia , Animales , Activación de Linfocitos , Ratones , Ratones Endogámicos BALB C , Ratones Transgénicos , Receptores de Antígenos de Linfocitos T/genética , Linfocitos T Citotóxicos/inmunologíaRESUMEN
Macrophage responses are regulated by multiple secreted factors as well as by cell surface receptors, including the inhibitory signals resulting from ligation of myeloid CD200 receptors (CD200R) by the widely distributed CD200. In the absence of CD200, animals display increased susceptibility to autoimmunity and earlier onset aggressive autoimmune disease. In these current experiments, an agonist monoclonal rat anti-mouse CD200R (DX109) antibody delivered a negative signal to bone marrow-derived macrophages, which suppressed interferon (IFN)gamma-mediated nitric oxide (NO) and interleukin-6 production. Experimental autoimmune uveoretinitis (EAU) was used as a model of organ-specific autoimmunity in the eye, a tissue with extensive neuronal and endothelial CD200 expression. In mice lacking CD200 (CD200(-/-)), increased numbers of retina-infiltrating macrophages displaying heightened NO responses were observed during EAU. In addition, we aimed to suppress disease by maintaining tonic suppression of macrophage activation via CD200R. Systemically administered DX109 monoclonal antibody suppressed EAU despite maintained T-cell proliferation and IFNgamma production. Furthermore, locally administered DX109 monoclonal antibody resulted in an earlier resolution of disease. These experiments demonstrate that promoting CD200R-mediated signaling can successfully prevent full expression of IFNgamma-mediated macrophage activation and protect against tissue damage during autoimmune responses.
Asunto(s)
Anticuerpos Monoclonales/farmacología , Enfermedades Autoinmunes/prevención & control , Activación de Macrófagos/efectos de los fármacos , Glicoproteínas de Membrana/inmunología , Retinitis/prevención & control , Uveítis/prevención & control , Animales , Anticuerpos Monoclonales/inmunología , Enfermedades Autoinmunes/patología , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/metabolismo , Células de la Médula Ósea/patología , Relación Dosis-Respuesta a Droga , Interferón gamma/metabolismo , Interferón gamma/farmacología , Interleucina-6/metabolismo , Lipopolisacáridos/farmacología , Activación de Macrófagos/inmunología , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Macrófagos/patología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Células Mieloides/efectos de los fármacos , Células Mieloides/metabolismo , Células Mieloides/patología , Óxido Nítrico Sintasa de Tipo II/metabolismo , Nitritos/metabolismo , Ratas , Retinitis/patología , Transducción de Señal/inmunología , Factores de Tiempo , Receptores Toll-Like/metabolismo , Uveítis/patologíaRESUMEN
InsHA mice express the haemagglutinin (HA) protein from influenza virus A/PR/8 H1N1 (PR8) as a self antigen on pancreatic islet beta cells. We have utilized these mice to investigate the ability of resting B cells expressing Kd to induce self-tolerance among naive KdHA-specific clone 4 CD8+ T cells. Adoptive transfer of KdHA-peptide-pulsed resting B cells into clone 4-->InsHA recipients resulted in the activation and proliferation of clone 4 CD8+ T cells throughout the peripheral lymphoid tissues. Significantly, proliferation was not associated with the acquisition of T cell effector function; as evidenced by a lack of interferon-gamma production and the complete absence of any autoimmune pathology even after immunization of recipient mice with PR8. These data demonstrate that resting B cells pulsed with self-epitopes can induce abortive activation of potentially self-reactive naive CD8+ T cells resulting in their functional deletion from the peripheral T-cell repertoire in the absence of any associated autoimmunity.