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1.
Immunol Rev ; 2024 May 29.
Artículo en Inglés | MEDLINE | ID: mdl-38809041

RESUMEN

Multiple sclerosis (MS) affects more than 2.8 million people worldwide but the distribution is not even. Although over 200 gene variants have been associated with susceptibility, studies of genetically identical monozygotic twin pairs suggest that the genetic make-up is responsible for only about 20%-30% of the risk to develop disease, while the rest is contributed by milieu factors. Recently, a new, unexpected player has entered the ranks of MS-triggering or facilitating elements: the human gut microbiota. In this review, we summarize the present knowledge of microbial effects on formation of a pathogenic autoreactive immune response targeting the distant central nervous system and delineate the approaches, both in people with MS and in MS animal models, which have led to this concept. Finally, we propose that a tight combination of investigations of human patients with studies of suitable animal models is the best strategy to functionally characterize disease-associated microbiota and thereby contribute to deciphering pathogenesis of a complex human disease.

2.
Proc Natl Acad Sci U S A ; 121(24): e2312837121, 2024 Jun 11.
Artículo en Inglés | MEDLINE | ID: mdl-38838013

RESUMEN

Through immune memory, infections have a lasting effect on the host. While memory cells enable accelerated and enhanced responses upon rechallenge with the same pathogen, their impact on susceptibility to unrelated diseases is unclear. We identify a subset of memory T helper 1 (Th1) cells termed innate acting memory T (TIA) cells that originate from a viral infection and produce IFN-γ with innate kinetics upon heterologous challenge in vivo. Activation of memory TIA cells is induced in response to IL-12 in combination with IL-18 or IL-33 but is TCR independent. Rapid IFN-γ production by memory TIA cells is protective in subsequent heterologous challenge with the bacterial pathogen Legionella pneumophila. In contrast, antigen-independent reactivation of CD4+ memory TIA cells accelerates disease onset in an autoimmune model of multiple sclerosis. Our findings demonstrate that memory Th1 cells can acquire additional TCR-independent functionality to mount rapid, innate-like responses that modulate susceptibility to heterologous challenges.


Asunto(s)
Inmunidad Innata , Memoria Inmunológica , Interferón gamma , Células TH1 , Células TH1/inmunología , Animales , Memoria Inmunológica/inmunología , Ratones , Interferón gamma/metabolismo , Interferón gamma/inmunología , Células T de Memoria/inmunología , Ratones Endogámicos C57BL , Legionella pneumophila/inmunología , Esclerosis Múltiple/inmunología , Interleucina-12/metabolismo , Interleucina-12/inmunología
3.
Proc Natl Acad Sci U S A ; 120(47): e2300733120, 2023 Nov 21.
Artículo en Inglés | MEDLINE | ID: mdl-37956299

RESUMEN

In multiple sclerosis (MS), pathogenic T cell responses are known to be important drivers of autoimmune inflammation. However, increasing evidence suggests an additional role for B cells, which may contribute to pathogenesis via antigen presentation and production of proinflammatory cytokines. However, these B cell effector functions are not featured well in classical experimental autoimmune encephalomyelitis (EAE) mouse models. Here, we compared properties of myelin oligodendrocyte glycoprotein (MOG)-specific and polyclonal B cells and developed an adjuvant-free cotransfer EAE mouse model, where highly activated, MOG-specific induced germinal center B cells provide the critical stimulus for disease development. We could show that high levels of MOG-specific immunoglobulin G (IgGs) are not required for EAE development, suggesting that antigen presentation and activation of cognate T cells by B cells may be important for pathogenesis. As our model allows for B cell manipulation prior to transfer, we found that overexpression of the proinflammatory cytokine interleukin (IL)-6 by MOG-specific B cells leads to an accelerated EAE onset accompanied by activation/expansion of the myeloid compartment rather than a changed T cell response. Accordingly, knocking out IL-6 or tumor necrosis factor α in MOG-specific B cells via CRISPR-Cas9 did not affect activation of pathogenic T cells. In summary, we generated a tool to dissect pathogenic B cell effector function in EAE development, which should improve our understanding of pathogenic processes in MS.


Asunto(s)
Encefalomielitis Autoinmune Experimental , Esclerosis Múltiple , Ratones , Animales , Citocinas , Autoinmunidad , Glicoproteína Mielina-Oligodendrócito , Interleucina-6 , Ratones Endogámicos C57BL
4.
Nat Immunol ; 13(10): 991-9, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-22961052

RESUMEN

Interleukin 17 (IL-17)-producing helper T cells (T(H)17 cells) are often present at the sites of tissue inflammation in autoimmune diseases, which has led to the conclusion that T(H)17 cells are main drivers of autoimmune tissue injury. However, not all T(H)17 cells are pathogenic; in fact, T(H)17 cells generated with transforming growth factor-ß1 (TGF-ß1) and IL-6 produce IL-17 but do not readily induce autoimmune disease without further exposure to IL-23. Here we found that the production of TGF-ß3 by developing T(H)17 cells was dependent on IL-23, which together with IL-6 induced very pathogenic T(H)17 cells. Moreover, TGF-ß3-induced T(H)17 cells were functionally and molecularly distinct from TGF-ß1-induced T(H)17 cells and had a molecular signature that defined pathogenic effector T(H)17 cells in autoimmune disease.


Asunto(s)
Enfermedades Autoinmunes/inmunología , Interleucina-17/biosíntesis , Células Th17/inmunología , Factor de Crecimiento Transformador beta1/inmunología , Factor de Crecimiento Transformador beta3/inmunología , Animales , Diferenciación Celular/inmunología , Humanos , Inflamación/inmunología , Interleucina-23/inmunología , Interleucina-6/inmunología , Ratones , Factor de Crecimiento Transformador beta1/metabolismo , Factor de Crecimiento Transformador beta3/metabolismo
5.
Proc Natl Acad Sci U S A ; 118(36)2021 09 07.
Artículo en Inglés | MEDLINE | ID: mdl-34479995

RESUMEN

Ectopic lymphoid tissue containing B cells forms in the meninges at late stages of human multiple sclerosis (MS) and when neuroinflammation is induced by interleukin (IL)-17 producing T helper (Th17) cells in rodents. B cell differentiation and the subsequent release of class-switched immunoglobulins have been speculated to occur in the meninges, but the exact cellular composition and underlying mechanisms of meningeal-dominated inflammation remain unknown. Here, we performed in-depth characterization of meningeal versus parenchymal Th17-induced rodent neuroinflammation. The most pronounced cellular and transcriptional differences between these compartments was the localization of B cells exhibiting a follicular phenotype exclusively to the meninges. Correspondingly, meningeal but not parenchymal Th17 cells acquired a B cell-supporting phenotype and resided in close contact with B cells. This preferential B cell tropism for the meninges and the formation of meningeal ectopic lymphoid tissue was partially dependent on the expression of the transcription factor Bcl6 in Th17 cells that is required in other T cell lineages to induce isotype class switching in B cells. A function of Bcl6 in Th17 cells was only detected in vivo and was reflected by the induction of B cell-supporting cytokines, the appearance of follicular B cells in the meninges, and of immunoglobulin class switching in the cerebrospinal fluid. We thus identify the induction of a B cell-supporting meningeal microenvironment by Bcl6 in Th17 cells as a mechanism controlling compartment specificity in neuroinflammation.


Asunto(s)
Enfermedades Neuroinflamatorias/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/metabolismo , Células Th17/metabolismo , Animales , Linfocitos B/inmunología , Comunicación Celular , Citocinas/metabolismo , Encefalomielitis Autoinmune Experimental/metabolismo , Femenino , Centro Germinal/inmunología , Inflamación/metabolismo , Activación de Linfocitos , Masculino , Meninges/inmunología , Meninges/metabolismo , Ratones , Ratones Endogámicos C57BL , Esclerosis Múltiple/metabolismo , Enfermedades Neuroinflamatorias/inmunología , Enfermedades Neuroinflamatorias/fisiopatología , Tejido Parenquimatoso/inmunología , Tejido Parenquimatoso/metabolismo , Proteínas Proto-Oncogénicas c-bcl-6/fisiología , Células Th17/inmunología , Células Th17/fisiología
6.
Immunity ; 37(2): 276-89, 2012 Aug 24.
Artículo en Inglés | MEDLINE | ID: mdl-22884313

RESUMEN

To initiate adaptive immunity, dendritic cells (DCs) move from parenchymal tissues to lymphoid organs by migrating along stromal scaffolds that display the glycoprotein podoplanin (PDPN). PDPN is expressed by lymphatic endothelial and fibroblastic reticular cells and promotes blood-lymph separation during development by activating the C-type lectin receptor, CLEC-2, on platelets. Here, we describe a role for CLEC-2 in the morphodynamic behavior and motility of DCs. CLEC-2 deficiency in DCs impaired their entry into lymphatics and trafficking to and within lymph nodes, thereby reducing T cell priming. CLEC-2 engagement of PDPN was necessary for DCs to spread and migrate along stromal surfaces and sufficient to induce membrane protrusions. CLEC-2 activation triggered cell spreading via downregulation of RhoA activity and myosin light-chain phosphorylation and triggered F-actin-rich protrusions via Vav signaling and Rac1 activation. Thus, activation of CLEC-2 by PDPN rearranges the actin cytoskeleton in DCs to promote efficient motility along stromal surfaces.


Asunto(s)
Movimiento Celular/fisiología , Células Dendríticas/metabolismo , Lectinas Tipo C/metabolismo , Glicoproteínas de Membrana/metabolismo , Actinas/metabolismo , Inmunidad Adaptativa/fisiología , Animales , Células Presentadoras de Antígenos/metabolismo , Plaquetas/metabolismo , Células Cultivadas , Células Dendríticas/inmunología , Embrión de Mamíferos , Células Endoteliales/metabolismo , Endotelio Linfático/citología , Endotelio Linfático/metabolismo , Femenino , Citometría de Flujo , Proteínas Fluorescentes Verdes/metabolismo , Humanos , Lectinas Tipo C/genética , Lectinas Tipo C/inmunología , Ganglios Linfáticos/citología , Ganglios Linfáticos/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Microscopía Confocal , Cadenas Ligeras de Miosina/metabolismo , Activación Plaquetaria , Embarazo , Proteínas Proto-Oncogénicas c-vav/metabolismo , Transducción de Señal/fisiología , Piel/citología , Piel/metabolismo , Técnicas de Cultivo de Tejidos , Proteína de Unión al GTP rac1/metabolismo , Proteína de Unión al GTP rhoA/metabolismo
7.
Immunity ; 35(6): 986-96, 2011 Dec 23.
Artículo en Inglés | MEDLINE | ID: mdl-22177922

RESUMEN

Ectopic lymphoid follicles are hallmarks of chronic autoimmune inflammatory diseases such as multiple sclerosis (MS), rheumatoid arthritis, Sjögren's syndrome, and myasthenia gravis. However, the effector cells and mechanisms that induce their development are unknown. Here we showed that in experimental autoimmune encephalomyelitis (EAE), the animal model of MS, Th17 cells specifically induced ectopic lymphoid follicles in the central nervous system (CNS). Development of ectopic lymphoid follicles was partly dependent on the cytokine interleukin 17 (IL-17) and on the cell surface molecule Podoplanin (Pdp), which was expressed on Th17 cells, but not on other effector T cell subsets. Pdp was also crucial for the development of secondary lymphoid structures: Pdp-deficient mice lacked peripheral lymph nodes and had a defect in forming normal lymphoid follicles and germinal centers in spleen and lymph node remnants. Thus, Th17 cells are uniquely endowed to induce tissue inflammation, characterized by ectopic lymphoid follicles within the target organ.


Asunto(s)
Encefalomielitis Autoinmune Experimental/inmunología , Células Th17/inmunología , Animales , Sistema Nervioso Central/inmunología , Sistema Nervioso Central/patología , Encefalomielitis Autoinmune Experimental/metabolismo , Encefalomielitis Autoinmune Experimental/patología , Tejido Linfoide/inmunología , Tejido Linfoide/patología , Glicoproteínas de Membrana/genética , Glicoproteínas de Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/metabolismo , Células Th17/metabolismo
8.
J Immunol ; 195(9): 4144-53, 2015 Nov 01.
Artículo en Inglés | MEDLINE | ID: mdl-26408664

RESUMEN

It is known that differentiation of Th17 cells is promoted by activation of STAT3 and inhibited by activation of STAT1. Although both transcription factors are activated by several cytokines, including IL-6, IL-21, and IL-27, each of these cytokines has a very different effect on Th17 differentiation, ranging from strong induction (IL-6) to strong inhibition (IL-27). To determine the molecular basis for these differences, we measured STAT3 and STAT1 activation profiles for IL-6, IL-21, and IL-27, as well as for cytokine pairs over time. We found that the ratio of activated STAT3/activated STAT1 is crucial in determining whether cytokines promote or inhibit Th17 differentiation. IL-6 and IL-21 induced p-STAT3/p-STAT1 ratios > 1, leading to the promotion of Th17 differentiation, whereas IL-27 or IL-6+IL-27 induced p-STAT3/p-STAT1 ratios < 1, resulting in inhibition of Th17 differentiation. Consistent with these findings, we show that IL-27 induces sufficient p-STAT3 to promote Th17 differentiation in the absence of STAT1. Furthermore, IL-27-induced STAT1-deficient T cells were indistinguishable from bona fide highly proinflammatory Th17 cells because they induced severe experimental autoimmune encephalomyelitis upon adoptive transfer. Our results suggest that the ratio of p-STAT3/p-STAT1 induced by a cytokine or cytokine pairs can be used to predict whether they induce a competent Th17-differentiation program.


Asunto(s)
Interleucina-27/farmacología , Factor de Transcripción STAT1/fisiología , Transducción de Señal/fisiología , Células Th17/efectos de los fármacos , Traslado Adoptivo , Animales , Diferenciación Celular/efectos de los fármacos , Interleucina-6/farmacología , Interleucinas/farmacología , Ratones , Ratones Endogámicos C57BL , Factor de Transcripción STAT3/fisiología , Células Th17/citología
10.
Immunol Rev ; 248(1): 122-39, 2012 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-22725958

RESUMEN

A number of autoimmune diseases, including multiple sclerosis, are mediated by self-reactive T cells that have escaped the deletional mechanisms of central tolerance. Usually, these T cells are kept at bay through peripheral tolerance mechanisms, including regulation through coinhibitory receptors and suppression by regulatory T cells. However, if these mechanisms fail, self-reactive T cells are activated and autoimmune responses ensue. This review outlines how the coinhibitory receptors CTLA-4 (cytotoxic T-lymphocyte antigen-4), PD-1 (programed death-1), Tim-3 (T-cell immunoglobulin- and mucin domain-containing molecule 3), and TIGIT (T-cell immunoreceptor with immunoglobulin and ITIM domains) act at different checkpoints to inhibit autoreactive T cells and suppress the development of central nervous system autoimmunity. Loss of each of these receptors predisposes to autoimmunity, indicating a non-redundant role in maintaining peripheral tolerance. At the same time, their functional patterns seem to overlap to a large degree. Therefore, we propose that only the concerted action of a combination of inhibitory receptors is able to maintain peripheral tolerance and prevent autoimmunity.


Asunto(s)
Autoinmunidad/inmunología , Sistema Nervioso Central/inmunología , Animales , Enfermedades Autoinmunes del Sistema Nervioso/genética , Enfermedades Autoinmunes del Sistema Nervioso/inmunología , Autoinmunidad/genética , Antígeno CTLA-4/genética , Antígeno CTLA-4/inmunología , Sistema Nervioso Central/metabolismo , Humanos , Receptores Inmunológicos/genética , Receptores Inmunológicos/inmunología , Linfocitos T Colaboradores-Inductores/inmunología , Linfocitos T Colaboradores-Inductores/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo
11.
Front Immunol ; 13: 755900, 2022.
Artículo en Inglés | MEDLINE | ID: mdl-35185870

RESUMEN

The key role of B cells in the pathophysiology of multiple sclerosis (MS) is supported by the presence of oligoclonal bands in the cerebrospinal fluid, by the association of meningeal ectopic B cell follicles with demyelination, axonal loss and reduction of astrocytes, as well as by the high efficacy of B lymphocyte depletion in controlling inflammatory parameters of MS. Here, we use a spontaneous model of experimental autoimmune encephalomyelitis (EAE) to study the clonality of the B cell response targeting myelin oligodendrocyte glycoprotein (MOG). In particular, 94% of SJL/j mice expressing an I-As: MOG92-106 specific transgenic T cell receptor (TCR1640) spontaneously develop a chronic paralytic EAE between the age of 60-500 days. The immune response is triggered by the microbiota in the gut-associated lymphoid tissue, while there is evidence that the maturation of the autoimmune demyelinating response might occur in the cervical lymph nodes owing to local brain drainage. Using MOG-protein-tetramers we tracked the autoantigen-specific B cells and localized their enrichment to the cervical lymph nodes and among the brain immune infiltrate. MOG-specific IgG1 antibodies were detected in the serum of diseased TCR1640 mice and proved pathogenic upon adoptive transfer into disease-prone recipients. The ontogeny of the MOG-specific humoral response preceded disease onset coherent with their contribution to EAE initiation. This humoral response was, however, not sufficient for disease induction as MOG-antibodies could be detected at the age of 69 days in a model with an average age of onset of 197 days. To assess the MOG-specific B cell repertoire we FACS-sorted MOG-tetramer binding cells and clonally expand them in vitro to sequence the paratopes of the IgG heavy chain and kappa light chains. Despite the fragility of clonally expanding MOG-tetramer binding effector B cells, our results indicate the selection of a common CDR-3 clonotype among the Igk light chains derived from both disease-free and diseased TCR1640 mice. Our study demonstrates the pre-clinical mobilization of the MOG-specific B cell response within the brain-draining cervical lymph nodes, and reiterates that MOG antibodies are a poor biomarker of disease onset and progression.


Asunto(s)
Linfocitos B/inmunología , Encefalomielitis Autoinmune Experimental/inmunología , Glicoproteína Mielina-Oligodendrócito/inmunología , Receptores de Antígenos de Linfocitos T/inmunología , Animales , Autoanticuerpos/inmunología , Autoantígenos/inmunología , Linfocitos B/citología , Encéfalo/metabolismo , Encéfalo/patología , Modelos Animales de Enfermedad , Encefalomielitis Autoinmune Experimental/patología , Encefalomielitis Autoinmune Experimental/fisiopatología , Femenino , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Esclerosis Múltiple/inmunología , Esclerosis Múltiple/patología , Glicoproteína Mielina-Oligodendrócito/genética
12.
Elife ; 112022 12 13.
Artículo en Inglés | MEDLINE | ID: mdl-36512388

RESUMEN

Neuroinflammation after stroke is characterized by the activation of resident microglia and the invasion of circulating leukocytes into the brain. Although lymphocytes infiltrate the brain in small number, they have been consistently demonstrated to be the most potent leukocyte subpopulation contributing to secondary inflammatory brain injury. However, the exact mechanism of how this minimal number of lymphocytes can profoundly affect stroke outcome is still largely elusive. Here, using a mouse model for ischemic stroke, we demonstrated that early activation of microglia in response to stroke is differentially regulated by distinct T cell subpopulations - with TH1 cells inducing a type I INF signaling in microglia and regulatory T cells (TREG) cells promoting microglial genes associated with chemotaxis. Acute treatment with engineered T cells overexpressing IL-10 administered into the cisterna magna after stroke induces a switch of microglial gene expression to a profile associated with pro-regenerative functions. Whereas microglia polarization by T cell subsets did not affect the acute development of the infarct volume, these findings substantiate the role of T cells in stroke by polarizing the microglial phenotype. Targeting T cell-microglia interactions can have direct translational relevance for further development of immune-targeted therapies for stroke and other neuroinflammatory conditions.


Asunto(s)
Isquemia Encefálica , Accidente Cerebrovascular , Humanos , Microglía/metabolismo , Isquemia Encefálica/metabolismo , Encéfalo/metabolismo , Transducción de Señal/fisiología
13.
J Clin Invest ; 130(9): 4587-4600, 2020 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-32484796

RESUMEN

Th cells integrate signals from their microenvironment to acquire distinct specialization programs for efficient clearance of diverse pathogens or for immunotolerance. Ionic signals have recently been demonstrated to affect T cell polarization and function. Sodium chloride (NaCl) was proposed to accumulate in peripheral tissues upon dietary intake and to promote autoimmunity via the Th17 cell axis. Here, we demonstrate that high-NaCl conditions induced a stable, pathogen-specific, antiinflammatory Th17 cell fate in human T cells in vitro. The p38/MAPK pathway, involving NFAT5 and SGK1, regulated FoxP3 and IL-17A expression in high-NaCl conditions. The NaCl-induced acquisition of an antiinflammatory Th17 cell fate was confirmed in vivo in an experimental autoimmune encephalomyelitis (EAE) mouse model, which demonstrated strongly reduced disease symptoms upon transfer of T cells polarized in high-NaCl conditions. However, NaCl was coopted to promote murine and human Th17 cell pathogenicity, if T cell stimulation occurred in a proinflammatory and TGF-ß-low cytokine microenvironment. Taken together, our findings reveal a context-dependent, dichotomous role for NaCl in shaping Th17 cell pathogenicity. NaCl might therefore prove beneficial for the treatment of chronic inflammatory diseases in combination with cytokine-blocking drugs.


Asunto(s)
Microambiente Celular/efectos de los fármacos , Citocinas/inmunología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Cloruro de Sodio Dietético/farmacología , Células Th17/inmunología , Animales , Microambiente Celular/inmunología , Citocinas/genética , Humanos , Inflamación/genética , Inflamación/inmunología , Inflamación/patología , Sistema de Señalización de MAP Quinasas/genética , Sistema de Señalización de MAP Quinasas/inmunología , Ratones , Ratones Transgénicos , Células Th17/patología
14.
Front Immunol ; 7: 451, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27826298

RESUMEN

Multiple sclerosis (MS) is an autoimmune disease characterized by chronic inflammation in the central nervous system (CNS), which results in permanent neuronal damage and substantial disability in patients. Autoreactive T cells are important drivers of the disease; however, the efficacy of B cell depleting therapies uncovered an essential role for B cells in disease pathogenesis. They can contribute to inflammatory processes via presentation of autoantigen, secretion of pro-inflammatory cytokines, and production of pathogenic antibodies. Recently, B cell aggregates reminiscent of tertiary lymphoid organs (TLOs) were discovered in the meninges of MS patients, leading to the hypothesis that differentiation and maturation of autopathogenic B and T cells may partly occur inside the CNS. Since these structures were associated with a more severe disease course, it is extremely important to gain insight into the mechanism of induction, their precise function, and clinical significance. Mechanistic studies in patients are limited. However, a few studies in the MS animal model experimental autoimmune encephalomyelitis (EAE) recapitulate TLO formation in the CNS and provide new insight into CNS TLO features, formation, and function. This review summarizes what we know so far about CNS TLOs in MS and what we have learned about them from EAE models. It also highlights the areas that are in need of further experimental work, as we are just beginning to understand and evaluate the phenomenon of CNS TLOs.

15.
J Clin Invest ; 125(1): 129-40, 2015 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-25415436

RESUMEN

Podoplanin (PDPN, also known as Gp38) is highly expressed on the surface of lymphatic endothelial cells, where it regulates development of lymphatic vessels. We have recently observed that PDPN is also expressed on effector T cells that infiltrate target tissues during autoimmune inflammation; however, the function of PDPN in T cells is largely unclear. Here, we demonstrated that global deletion of Pdpn results in exaggerated T cell responses and spontaneous experimental autoimmune encephalomyelitis (EAE) in mice with a susceptible genetic background. In contrast, T cell-specific overexpression of PDPN resulted in profound defects in IL-7-mediated T cell expansion and survival. Consequently, these animals exhibited a more rapid resolution of CNS inflammation, characterized by a reduced effector CD4+ T cell population in the CNS. Mice harboring a T cell-specific deletion of Pdpn developed exacerbated EAE, with increased accumulation of effector CD4+ T cells in the CNS. Transcriptional profiling of naturally occurring PDPN+ effector T cells in the CNS revealed increased expression of other inhibitory receptors, such as Pd1 and Tim3, and decreased expression of prosurvival factors, including Il7ra. Together, our data suggest that PDPN functions as an inhibitory molecule on T cells, thereby promoting tissue tolerance by limiting long-term survival and maintenance of CD4+ effector T cells in target organs.


Asunto(s)
Linfocitos T CD4-Positivos/inmunología , Glicoproteínas de Membrana/fisiología , Animales , Linfocitos T CD4-Positivos/metabolismo , Supervivencia Celular , Células Cultivadas , Encefalomielitis Autoinmune Experimental/inmunología , Encefalomielitis Autoinmune Experimental/patología , Linfopenia/inmunología , Ratones de la Cepa 129 , Ratones Endogámicos C57BL , Ratones Noqueados
16.
Curr Opin Immunol ; 28: 42-8, 2014 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-24594517

RESUMEN

Th17 cells are a subset of CD4+ T helper cells that play an important role in host defense and have been strongly associated with the pathogenesis of autoimmunity. The immense research effort on Th17 cells has benefited in recent years from major breakthroughs in genomic profiling technologies. The picture emerging from these studies has led us away from thinking about T cell differentiation in terms of rigid, separate pathways that give rise to canonical 'types'. Instead, it has encouraged us to understand T cell differentiation and function through a complex network of transcriptional regulators that can lead to different and potentially plastic cell states. This review summarizes some of the lessons we have learned from these studies about the identity, interplay, and function of the factors that are involved in Th17 cell differentiation, effector functions and plasticity. It also highlights some applications, challenges, and limitations of large-scale systematic analyses of T cell function.


Asunto(s)
Células Th17/inmunología , Animales , Diferenciación Celular , Regulación de la Expresión Génica , Genómica , Humanos , Modelos Inmunológicos , Células Th17/citología , Transcripción Genética
17.
Curr Opin Immunol ; 23(6): 702-6, 2011 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-21899997

RESUMEN

Th17 cells have been shown to be strong inducers of tissue inflammation and autoimmune diseases. However, not all Th17 cells are pathogenic and increasing data suggest that Th17 cells may come in different flavors. Thus, Th17 cells cannot be described using a narrow schematic, but instead Th17 cells comprise a wide spectrum with a range of effector phenotypes. Here, we review the key factors that generate such diversity, as well as the cytokines and transcription factors that are differentially expressed in pathogenic and nonpathogenic Th17 cells. This new knowledge can be used to identify molecules that make Th17 cells pathogenic and determine how these cells could be targeted to suppress autoimmune diseases.


Asunto(s)
Células Th17/inmunología , Animales , Factor Estimulante de Colonias de Granulocitos y Macrófagos/inmunología , Humanos , Interferón gamma/biosíntesis , Interferón gamma/inmunología , Interleucina-10/inmunología , Factores de Transcripción/inmunología
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