scholarly journals Mechanisms of acquired thymic tolerance in experimental autoimmune encephalomyelitis: thymic dendritic-enriched cells induce specific peripheral T cell unresponsiveness in vivo.

1995 ◽  
Vol 182 (2) ◽  
pp. 357-366 ◽  
Author(s):  
S J Khoury ◽  
L Gallon ◽  
W Chen ◽  
K Betres ◽  
M E Russell ◽  
...  
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Autoimmune Encephalomyelitis ◽  
Activated T Cells ◽  
Lewis Rats ◽  
Intrathymic Injection ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE), an experimental model for the study of multiple sclerosis, is an autoimmune disease of the central nervous system that can be induced in a number of species by immunization with myelin basic protein (MBP). MBP-reactive CD4+ T cells, predominantly expressing the V beta 8.2 T cell receptor (TCR), migrate from the peripheral lymphoid organs and initiate the inflammatory response in the brain. We have previously shown that a single intrathymic injection of MBP or its major encephalitogenic peptide (p71-90), but not a nonencephalitogenic peptide (p21-40), induces antigen-specific systemic tolerance and inhibits the induction of EAE in Lewis rats. In this study, we investigated the mechanisms of induction and maintenance of acquired thymic tolerance in this model. First, we investigated which thymic cell is responsible for "induction" of systemic tolerance. Thymic dendritic-enriched cells, isolated by plastic adherence, when incubated in vitro with p71-90 and injected intravenously into Lewis rats, were capable of preventing the development of EAE, but his protection was lost in thymectomized recipients. In addition, intravenous injection of thymic dendritic cells isolated from animals that had been previously injected intrathymically with p71-90 but not p21-40 also prevented the development of EAE. Second, to determine the "effector" mechanisms involved in acquired thymic tolerance, we compared TCR expression in the brains of animals with actively induced EAE with TCR expression in animals that received intrathymic injection of p71-90 or p21-40. Using a semiquantitative reverse transcription-polymerase chain reaction (RT-PCR) technique, we found increased expression of CD4 and V beta 8.2 message in brains of immunized animals compared with those of naive animals. In animals intrathymically injected with p71-90 but not p21-40, CD4 and V beta 8.2 transcript levels were significantly reduced compared with immunized controls. Immunohistologic studies of brain tissue and spleens with specific V beta 8.2 and control V beta 10 monoclonal antibodies confirmed these observations in vivo. These findings, taken together with recent data demonstrating that activated T cells circulate through the thymus, suggest that interaction of thymic dendritic cells with specific TCR of activated peripheral T cells can lead to inactivation of these antigen-specific cells and confirm the role of V beta 8.2-expressing T cells in EAE.

scholarly journals Priming of Myelin-Specific T Cells in the Absence of Dendritic Cells Results in Accelerated Development of Experimental Autoimmune Encephalomyelitis

2020 ◽  
Author(s):  
Thaiphi Luu ◽  
Julie F. Cheung ◽  
Hanspeter Waldner
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Cell Responses ◽  
Proteolipid Protein ◽  
Cell Receptor ◽  
Autoimmune Encephalomyelitis ◽  
Cell Responses ◽  
Experimental Autoimmune

AbstractExperimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis (MS), is predominantly mediated by pro-inflammatory CD4+ T cell responses to CNS antigens, including myelin proteolipid protein (PLP). Dendritic cells (DCs) are considered critical for inducing T cell responses against infectious agents, but the importance of DCs in priming self-reactive CD4+ T cells in autoimmune disease such as MS has been unclear.To determine the requirement of DCs in PLP-specific CD4+ T cell responses and EAE, we genetically deleted CD11c+ DCs in PLP T cell receptor (TCR) transgenic SJL mice constitutively. DC deficiency did not impair the development, selection or the pathogenic function of PLP-specific CD4+ T cells in these mice, and resulted in accelerated spontaneous EAE compared to DC sufficient controls. In addition, using a genetic approach to ablate DCs conditionally in SJL mice, we show that CD11c+ DCs were dispensable for presenting exogenous or endogenous myelin antigen to PLP-specific T cells and for promoting pro-inflammatory T cell responses and severe EAE. Our findings demonstrate that constitutive or conditional ablation of CD11c+ DCs diminished self-tolerance to PLP autoantigen. They further show that in the absence of DCs, non-DCs can efficiently present CNS myelin antigens such as PLP to self-reactive T cells, resulting in accelerated onset of spontaneous or induced EAE.

scholarly journals Priming of myelin-specific T cells in the absence of dendritic cells results in accelerated development of Experimental Autoimmune Encephalomyelitis

PLoS ONE ◽  
2021 ◽  
Vol 16 (4) ◽  
pp. e0250340
Author(s):  
Thaiphi Luu ◽  
Julie F. Cheung ◽  
Jennifer Baccon ◽  
Hanspeter Waldner
Keyword(s):  
T Cells ◽  
Dendritic Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
T Cell Responses ◽  
Proteolipid Protein ◽  
Cell Receptor ◽  
Autoimmune Encephalomyelitis ◽  
Cell Responses ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an established animal model of multiple sclerosis (MS). Inflammatory CD4+ T cell responses directed against CNS antigens, including myelin proteolipid protein (PLP), are key mediators of EAE. Dendritic cells (DCs) are critical for the induction of T cell responses against infectious agents. However, the importance of DCs in priming self-reactive CD4+ T cells in autoimmune disease such as MS has been unclear. To determine the requirement of DCs in PLP-specific CD4+ T cell responses and EAE, we genetically deleted CD11c+ DCs in PLP T cell receptor (TCR) transgenic SJL mice constitutively. DC deficiency did not impair the development, selection or the pathogenic function of PLP-specific CD4+ T cells in these mice, and resulted in accelerated spontaneous EAE compared to DC sufficient controls. In addition, using a genetic approach to ablate DCs conditionally in SJL mice, we show that CD11c+ DCs were dispensable for presenting exogenous or endogenous myelin antigen to PLP-specific T cells and for promoting pro-inflammatory T cell responses and severe EAE. Our findings demonstrate that constitutive or conditional ablation of CD11c+ DCs diminished self-tolerance to PLP autoantigen. They further show that in the absence of DCs, non-DCs can efficiently present CNS myelin antigens such as PLP to self-reactive T cells, resulting in accelerated onset of spontaneous or induced EAE.

scholarly journals Selective targeting of regulatory T cells with CD28 superagonists allows effective therapy of experimental autoimmune encephalomyelitis

2005 ◽  
Vol 202 (3) ◽  
pp. 445-455 ◽  
Author(s):  
Niklas Beyersdorf ◽  
Stefanie Gaupp ◽  
Karen Balbach ◽  
Jens Schmidt ◽  
Klaus V. Toyka ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Cell Subset ◽  
High Dose ◽  
Autoimmune Encephalomyelitis ◽  
Lewis Rats ◽  
Experimental Autoimmune

CD4+CD25+ regulatory T cells (T reg cells) play a key role in controlling autoimmunity and inflammation. Therefore, therapeutic agents that are capable of elevating numbers or increasing effector functions of this T cell subset are highly desirable. In a previous report we showed that a superagonistic monoclonal antibody specific for rat CD28 (JJ316) expands and activates T reg cells in vivo and upon short-term in vitro culture. Here we demonstrate that application of very low dosages of the CD28 superagonist into normal Lewis rats is sufficient to induce T reg cell expansion in vivo without the generalized lymphocytosis observed with high dosages of JJ316. Single i.v. administration of a low dose of the CD28 superagonist into Dark Agouti (DA) rats or Lewis rats that suffered from experimental autoimmune encephalomyelitis (EAE) proved to be highly and equally efficacious as high-dose treatment. Finally, we show that T reg cells that were isolated from CD28-treated animals displayed enhanced suppressive activity toward myelin basic protein–specific T cells in vitro, and, upon adoptive transfer, protected recipients from EAE. Our data indicate that this class of CD28-specific monoclonal antibodies targets CD4+CD25+ T reg cells and provides a novel means for the effective treatment of multiple sclerosis and other autoimmune diseases.

scholarly journals Mgat5 Deficiency in T Cells and Experimental Autoimmune Encephalomyelitis

2011 ◽  
Vol 2011 ◽  
pp. 1-6 ◽  
Author(s):  
Ani Grigorian ◽  
Michael Demetriou
Keyword(s):  
T Cells ◽  
T Cell ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Demyelinating Disease ◽  
Cell Receptor ◽  
Protein Glycosylation ◽  
Autoimmune Encephalomyelitis ◽  
Glycosylation Pathway ◽  
Experimental Autoimmune ◽  
Surface Glycoproteins

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease initiated by autoreactive T cells. Mgat5, a gene in the Asn (N-) linked protein glycosylation pathway, associates with MS severity and negatively regulates experimental autoimmune encephalomyelitis (EAE) and spontaneous inflammatory demyelination in mice. N-glycan branching by Mgat5 regulates interaction of surface glycoproteins with galectins, forming a molecular lattice that differentially controls the concentration of surface glycoproteins. T-cell receptor signaling, T-cell proliferation, TH1 differentiation, and CTLA-4 endocytosis are inhibited by Mgat5 branching. Non-T cells also contribute to MS pathogenesis and express abundant Mgat5 branched N-glycans. Here we explore whether Mgat5 deficiency in myelin-reactive T cells is sufficient to promote demyelinating disease. Adoptive transfer of myelin-reactive Mgat5−/− T cells into Mgat5+/+ versus Mgat5−/− recipients revealed more severe EAE in the latter, suggesting that Mgat5 branching deficiency in recipient naive T cells and/or non-T cells contribute to disease pathogenesis.

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