scholarly journals Tumor Necrosis Factor-Related Apoptosis-Inducing Ligand Inhibits Experimental Autoimmune Thyroiditis by the Expansion of CD4+CD25+ Regulatory T Cells

Endocrinology ◽  
2008 ◽  
Vol 150 (4) ◽  
pp. 2000-2007 ◽  
Author(s):  
Su He Wang ◽  
Gwo-Hsiao Chen ◽  
Yongyi Fan ◽  
Mary Van Antwerp ◽  
James R. Baker
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Autoimmune Thyroiditis ◽  
Rabbit Model ◽  
Experimental Autoimmune Thyroiditis ◽  
Autoimmune Encephalomyelitis ◽  
Necrosis Factor ◽  
Experimental Autoimmune

There have been several reports that TNF-related apoptosis-inducing ligand (TRAIL) has the ability to suppress the development of experimental autoimmune diseases, including a mouse model of experimental autoimmune encephalomyelitis, a rabbit model of rheumatoid arthritis, type 1 diabetes mellitus, in mice and experimental autoimmune thyroiditis (EAT) in mice. However, the mechanism underlying TRAIL effect is not well defined. In the present study, we specifically examined TRAIL effects on CD4+CD25+ regulatory T cells. CD4+CD25+ T cells prepared from mouse thyroglobulin (mTg)-immunized CBA/J mice proliferate in the presence of TRAIL and dendritic cells in vitro. These CD4+CD25+ T cells included both CD4+CD25+CD45RBLow (regulatory) and CD4+CD25+CD45RBHigh (effector) T cells. Our results demonstrated that mTg-immunized mice treated with TRAIL showed significant increases in the number of CD4+CD25+CD45RBLow T cells compared with mice immunized with mTg alone. CD4+CD25+CD45RBLow T cells expressed much higher levels of the forkhead family transcription factor, IL-10, and TGFβ1 than CD4+CD25+CD45RBHigh T cells, and these cells can completely suppress the proliferation of the mTg-primed splenocytes in lower concentrations than the unfractionated CD4+CD25+ T cells. Furthermore, transfer of these cells into CBA/J mice prior to mTg-primed splenocyte injection could markedly reduce the frequency and severity of EAT development. CD4+CD25+CD45RBLow T cells were more effective at suppressing histological thyroiditis than unfractionated cells. These results indicated that TRAIL can increase the number of mTg-specific CD4+CD25+CD45RBLow T cells, inhibiting autoimmune responses and preventing the progression of EAT. These findings reveal a novel mechanism by which TRAIL could inhibit autoimmune disease.

scholarly journals CXCL12 (SDF-1α) suppresses ongoing experimental autoimmune encephalomyelitis by selecting antigen-specific regulatory T cells

2008 ◽  
Vol 205 (11) ◽  
pp. 2643-2655 ◽  
Author(s):  
Moran Meiron ◽  
Yaniv Zohar ◽  
Rachel Anunu ◽  
Gizi Wildbaum ◽  
Nathan Karin
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Neutralizing Antibodies ◽  
Regulatory Function ◽  
Th1 Cells ◽  
Dependent Manner ◽  
Autoimmune Encephalomyelitis ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is a T cell–mediated autoimmune disease of the central nervous system induced by antigen-specific effector Th17 and Th1 cells. We show that a key chemokine, CXCL12 (stromal cell–derived factor 1α), redirects the polarization of effector Th1 cells into CD4+CD25−Foxp3−interleukin (IL) 10high antigen-specific regulatory T cells in a CXCR4-dependent manner, and by doing so acts as a regulatory mediator restraining the autoimmune inflammatory process. In an attempt to explore the therapeutic implication of these findings, we have generated a CXCL12-immunoglobulin (Ig) fusion protein that, when administered during ongoing EAE, rapidly suppresses the disease in wild-type but not IL-10–deficient mice. Anti–IL-10 neutralizing antibodies could reverse this suppression. The beneficial effect included selection of antigen-specific T cells that were CD4+CD25−Foxp3−IL-10high, which could adoptively transfer disease resistance, and suppression of Th17 selection. However, in vitro functional analysis of these cells suggested that, even though CXCL12-Ig–induced tolerance is IL-10 dependent, IL-10–independent mechanisms may also contribute to their regulatory function. Collectively, our results not only demonstrate, for the first time, that a chemokine functions as a regulatory mediator, but also suggest a novel way for treating multiple sclerosis and possibly other inflammatory autoimmune diseases.

Induction of experimental autoimmune thyroiditis in mice with in vitro activated splenic T cells

1985 ◽  
Vol 93 (1) ◽  
pp. 132-143 ◽  
Author(s):  
Helen Braley-Mullen ◽  
Michael Johnson ◽  
Gordon C. Sharp ◽  
Michael Kyriakos
Keyword(s):  
T Cells ◽  
Autoimmune Thyroiditis ◽  
Experimental Autoimmune Thyroiditis ◽  
Experimental Autoimmune

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 Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Lin Luo ◽  
Xianzhen Hu ◽  
Michael L. Dixon ◽  
Brandon J. Pope ◽  
Jonathan D. Leavenworth ◽  
...  
Keyword(s):  
T Cells ◽  
Regulatory T Cells ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Myeloid Cells ◽  
Autoimmune Encephalomyelitis ◽  
Gm Csf ◽  
Cns Autoimmunity ◽  
The Impact ◽  
Experimental Autoimmune

Abstract Background Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Methods To determine the impact of dysregulated regulatory T cells (Tregs), TFR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. Results Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased TFH-Ab responses, more IgE deposition in the CNS, and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. Conclusions Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

Sign in / Sign up

Export Citation Format

Share Document