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Discrete TCR repertoires and CDR3 features distinguish effector and Foxp3+ regulatory T lymphocytes in myelin oligodendrocyte glycoprotein-induced experimental allergic encephalomyelitis.

ABSTRACT: Regulatory T lymphocytes (Tregs) expressing the Foxp3 transcription factor are critical modulators of autoimmunity. Foxp3(+) Tregs may develop in the thymus as a population distinct from conventional Foxp3(-) ?? T cells (Tconvs). Alternatively, plasticity in Foxp3 expression may allow for the interconversion of mature Tregs and Tconvs. We examined >160,000 TCR sequences from Foxp3(+) or Foxp3(-) populations in the spleens or CNS of wild-type mice with experimental allergic encephalomyelitis to determine their relatedness and identify distinguishing TCR features. Our results indicate that the CNS-infiltrating Tregs and Tconvs arise predominantly from distinct sources. The repertoires of CNS Treg or Tconv TCRs showed limited overlap with heterologous populations in both the CNS and the spleen, indicating that they are largely unrelated. Indeed, Treg and Tconv TCRs in the CNS were significantly less related than those populations in the spleen. In contrast, CNS Treg and Tconv repertoires strongly intersected those of the homologous cell type in the spleen. High-frequency sequences more likely to be disease associated showed similar results, and some public TCRs demonstrated Treg- or Tconv-specific motifs. Different charge characteristics and amino acid use preferences were identified in the CDR3? of Tregs and Tconvs infiltrating the CNS, further indicating that their repertoires are qualitatively distinct. Therefore, discrete populations of Tregs and Tconvs that do not substantially interconvert respond during experimental allergic encephalomyelitis. Differences in sequence and physical characteristics distinguish Treg and Tconv TCRs and imply dissimilar Ag recognition properties.

SUBMITTER: Nguyen P

PROVIDER: S-EPMC2944006 | biostudies-literature | 2010 Oct

REPOSITORIES: biostudies-literature

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Discrete TCR repertoires and CDR3 features distinguish effector and Foxp3+ regulatory T lymphocytes in myelin oligodendrocyte glycoprotein-induced experimental allergic encephalomyelitis.

Nguyen Phuong P Liu Wei W Ma Jing J Manirarora Jean N JN Liu Xin X Cheng Cheng C Geiger Terrence L TL

Journal of immunology (Baltimore, Md. : 1950) 20100901 7

Regulatory T lymphocytes (Tregs) expressing the Foxp3 transcription factor are critical modulators of autoimmunity. Foxp3(+) Tregs may develop in the thymus as a population distinct from conventional Foxp3(-) αβ T cells (Tconvs). Alternatively, plasticity in Foxp3 expression may allow for the interconversion of mature Tregs and Tconvs. We examined >160,000 TCR sequences from Foxp3(+) or Foxp3(-) populations in the spleens or CNS of wild-type mice with experimental allergic encephalomyelitis to d ...[more]

PMID: 20810983

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Project description:Background: Myelin oligodendrocyte glycoprotein (MOG) antibody associated encephalomyelitis is increasingly being considered a distinct disease entity, with seizures and encephalopathy commonly reported. We investigated the clinical features of MOG-IgG positive patients presenting with seizures and/or encephalopathy in a single cohort. Methods: Consecutive patients with suspected idiopathic inflammatory demyelinating diseases were recruited from a tertiary University hospital in Guangdong province, China. Subjects with MOG-IgG seropositivity were analyzed according to whether they presented with or without seizure and/or encephalopathy. Results: Overall, 58 subjects seropositive for MOG-IgG were analyzed, including 23 (40%) subjects presenting with seizures and/or encephalopathy. Meningeal irritation (P = 0.030), fever (P = 0.001), headache (P = 0.001), nausea, and vomiting (P = 0.004) were more commonly found in subjects who had seizures and/or encephalopathy, either at presentation or during the disease course. Nonetheless, there was less optic nerve (4/23, 17.4%, P = 0.003) and spinal cord (6/16, 37.5%, P = 0.037) involvement as compared to subjects without seizures or encephalopathy. Most MOG encephalomyelitis subjects had cortical/subcortical lesions: 65.2% (15/23) in the seizures and/or encephalopathy group and 50.0% (13/26) in the without seizures or encephalopathy group. Cerebrospinal fluid (CSF) leukocytes were elevated in both groups. Subgroup analysis showed that 30% (7/23) MOG-IgG positive subjects with seizures and/or encephalopathy had been misdiagnosed for central nervous system infection on the basis of meningoencephalitis symptoms and elevated CSF leukocytes (P = 0.002). Conclusions: Seizures and encephalopathy are not rare in MOG encephalomyelitis, and are commonly associated with cortical and subcortical brain lesions. MOG-encephalomyelitis often presents with clinical meningoencephalitis symptoms and abnormal CSF findings mimicking central nervous system infection in pediatric and young adult patients.

Project description:BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is associated with local activation of microglia and astroglia, infiltration of activated macrophages and T cells, active degradation of myelin and damage to axons and neurons. The proposed role for CX3CL1 (fractalkine) in the control of microglia activation and leukocyte infiltration places this chemokine and its receptor CX3CR1 in a potentially strategic position to control key aspects in the pathological events that are associated with development of brain lesions in MS. In this study, we examine this hypothesis by analyzing the distribution, kinetics, regulation and cellular origin of CX3CL1 and CX3CR1 mRNA expression in the CNS of rats with an experimentally induced MS-like disease, myelin oligodendrocyte glycoprotein (MOG)-induced autoimmune encephalomyelitis (EAE). METHODS: The expression of CX3CL1 and its receptor CX3CR1 was studied with in situ hybridization histochemical detection of their mRNA with radio labeled cRNA probes in combination with immunohistochemical staining of phenotypic cell markers. Both healthy rat brains and brains from rats with MOG EAE were analyzed. In defined lesional stages of MOG EAE, the number of CX3CR1 mRNA-expressing cells and the intensity of the in situ hybridization signal were determined by image analysis. Data were statistically evaluated by ANOVA, followed by Tukey\primes multiple comparison test. RESULTS: Expression of CX3CL1 mRNA was present within neuronal-like cells located throughout the neuraxis of the healthy rat. Expression of CX3CL1 remained unaltered in the CNS of rats with MOG-induced EAE, with the exception of an induced expression in astrocytes within inflammatory lesions. Notably, the brain vasculature of healthy and encephalitic animals did not exhibit signs of CX3CL1 mRNA expression. The receptor, CX3CR1, was expressed by microglial cells in all regions of the healthy brain. Induction of MOG-induced EAE was associated with a distinct accumulation of CX3CR1 mRNA expressing cells within the inflammatory brain lesions, the great majority of which stained positive for markers of the microglia-macrophage lineage. Analysis in time-staged brain lesions revealed elevated levels of CX3CR1 mRNA in microglia in the periplaque zone, as well as a dramatically enhanced accumulation of CX3CR1 expressing cells within the early-active, late-active and inactive, demyelinated lesions. CONCLUSION: Our data demonstrate constitutive and regulated expression of the chemokine CX3CL1 and its receptor CX3CR1 by neurons/astrocytes and microglia, respectively, within the normal and inflamed rat brain. Our findings propose a mechanism by which neurons and reactive astrocytes may control migration and function of the surrounding microglia. In addition, the accumulation of CX3CR1 expressing cells other than microglia within the inflammatory brain lesions indicate a possible role for CX3CL1 in controlling invasion of peripheral leucocytes to the brain.

Dataset Information

Discrete TCR repertoires and CDR3 features distinguish effector and Foxp3+ regulatory T lymphocytes in myelin oligodendrocyte glycoprotein-induced experimental allergic encephalomyelitis.

Publications

Discrete TCR repertoires and CDR3 features distinguish effector and Foxp3+ regulatory T lymphocytes in myelin oligodendrocyte glycoprotein-induced experimental allergic encephalomyelitis.

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