Search results for "Autoimmune"

T helper 17 lineage differentiation is programmed by orphan nuclear receptors ROR alpha and ROR gamma.

2007

T cell functional differentiation is mediated by lineage-specific transcription factors. T helper 17 (Th17) has been recently identified as a distinct Th lineage mediating tissue inflammation. Retinoic acid receptor-related orphan receptor gamma (ROR gamma) was shown to regulate Th17 differentiation; ROR gamma deficiency, however, did not completely abolish Th17 cytokine expression. Here, we report Th17 cells highly expressed another related nuclear receptor, ROR alpha, induced by transforming growth factor-beta and interleukin-6 (IL-6), which is dependent on signal transducer and activator of transcription 3. Overexpression of ROR alpha promoted Th17 differentiation, possibly through the c…

Microglial activation milieu controls regulatory T cell responses.

2013

Abstract Although mechanisms leading to brain-specific inflammation and T cell activation have been widely investigated, regulatory mechanisms of local innate immune cells in the brain are only poorly understood. In this study, to our knowledge we show for the first time that MHC class II+CD40dimCD86dimIL-10+ microglia are potent inducers of Ag-specific CD4+Foxp3+ regulatory T cells (Tregs) in vitro. Microglia differentially regulated MHC class II expression, costimulatory molecules, and IL-10 depending on the amount of IFN-γ challenge and Ag dose, promoting either effector T cell or Treg induction. Microglia-induced Tregs were functionally active in vitro by inhibiting Ag-specific prolifer…

Dendritic Cells Ameliorate Autoimmunity in the CNS by Controlling the Homeostasis of PD-1 Receptor+ Regulatory T Cells

2012

SummaryMature dendritic cells (DCs) are established as unrivaled antigen-presenting cells (APCs) in the initiation of immune responses, whereas steady-state DCs induce peripheral T cell tolerance. Using various genetic approaches, we depleted CD11c+ DCs in mice and induced autoimmune CNS inflammation. Unexpectedly, mice lacking DCs developed aggravated disease compared to control mice. Furthermore, when we engineered DCs to present a CNS-associated autoantigen in an induced manner, we found robust tolerance that prevented disease, which coincided with an upregulation of the PD-1 receptor on antigen-specific T cells. Additionally, we showed that PD-1 was necessary for DC-mediated induction o…

Protection from experimental allergic encephalomyelitis by application of a bacterial superantigen

1992

Certain bacterial and viral T cell stimulating proteins ('superantigens') are known to be very potent activators of T cells with certain V beta receptors. When applied in vivo these molecules induce anergy in those T cells responding to them. In this study we have investigated the influence of staphylococcal enterotoxins (SE) on myelin basic protein (MBP)-specific T cells in Lewis rats. As MBP-specific T cells in rats belong exclusively to the V beta 8.2+ CD4+ subset, the induction of experimental allergic encephalomyelitis (EAE) allows for an estimation of the functional state of the respective V beta-bearing T cells after enterotoxin-induced activation. In vitro, various MBP-specific T ce…

Inhibition of the mixed lymphocyte reaction by T cell vaccination

1990

Immunization with attenuated activated autoreactive T cell lines and clones induces a response in syngeneic animals which can induce protection or recovery from autoimmune disease. This process has been termed T cell vaccination. The aim of the present study was to investigate the effect of immunization with MHC-reactive T cells on the mixed lymphocyte reaction (MLR). By injecting attenuated activated T cells primed for an alloantigen, we markedly reduced the MLR in both rats and mice. This depression appeared to be mediated by active suppression; lymphoid cells from T cell-vaccinated animals suppressed the MLR responsiveness of T cells from naive animals. Suppression of the MLR was not res…

The protein tyrosine kinase Tec regulates a CD44highCD62L- Th17 subset.

2010

Abstract The generation of Th17 cells has to be tightly controlled during an immune response. In this study, we report an increase in a CD44highCD62L− Th17 subset in mice deficient for the protein tyrosine kinase Tec. CD44highCD62L− Tec−/− CD4+ T cells produced enhanced IL-17 upon activation, showed increased expression levels of IL-23R and RORγt, and IL-23–mediated expansion of Tec−/− CD4+ T cells led to an increased production of IL-17. Tec−/− mice immunized with heat-killed Streptococcus pneumoniae displayed increased IL-17 expression levels in the lung postinfection with S. pneumoniae, and this correlated with enhanced pneumococcal clearance and reduced lung inflammation compared with T…

Pre- and postsynaptic type-1 cannabinoid receptors control the alterations of glutamate transmission in experimental autoimmune encephalomyelitis

2013

Type-1 cannabinoid receptors (CB1R) are important regulators of the neurodegenerative damage in multiple sclerosis (MS) and in experimental autoimmune encephalomyelitis (EAE). In GABAergic striatal neurons, CB1R stimulation exerts protective effects by limiting inflammation-induced potentiation of glutamate-mediated spontaneous excitatory postsynaptic currents (sEPSCs). Here we show that CB1R located on GABAergic or on glutamatergic neurons are differentially involved in the pre- and postsynaptic alterations of sEPSCs caused by EAE in the striatum. After induction of EAE, mice selectively lacking CB1R on GABAergic neurons (GABA-CB1R-KO) showed exacerbated alterations of sEPSC duration in GA…

Immunoregulation: studies of physiological and therapeutic autoreactivity by T cell vaccination

1992

Persistent inflammation alters the function of the endogenous brain stem cell compartment

2008

Endogenous neural stem/precursor cells (NPCs) are considered a functional reservoir for promoting tissue homeostasis and repair after injury, therefore regenerative strategies that mobilize these cells have recently been proposed. Despite evidence of increased neurogenesis upon acute inflammatory insults (e.g. ischaemic stroke), the plasticity of the endogenous brain stem cell compartment in chronic CNS inflammatory disorders remains poorly characterized. Here we show that persistent brain inflammation, induced by immune cells targeting myelin, extensively alters the proliferative and migratory properties of subventricular zone (SVZ)-resident NPCs in vivo leading to significant accumulation…

IL-17A and IL-17F do not contribute vitally to autoimmune neuro-inflammation in mice

2009

The clear association of Th17 cells with autoimmune pathogenicity implicates Th17 cytokines as critical mediators of chronic autoimmune diseases such as EAE. To study the impact of IL-17A on CNS inflammation, we generated transgenic mice in which high levels of expression of IL-17A could be initiated after Cre-mediated recombination. Although ubiquitous overexpression of IL-17A led to skin inflammation and granulocytosis, T cell–specific IL-17A overexpression did not have a perceptible impact on the development and health of the mice. In the context of EAE, neither the T cell–driven overexpression of IL-17A nor its complete loss had a major impact on the development of clinical disease. Sin…