The Dendritic Cell-T Cell Synapse as a Determinant of Autoimmune Pathogenesis

Iruretagoyena, Mirentxu; Wiesendanger, Margrit; Kalergis, Alexis M.

doi:10.2174/138161206775193145

Cited by 28 publications

(31 citation statements)

References 173 publications

(228 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…We and others have shown that, while immature DC express predominantly FccRIIb, targeting antigens to FccRIII can significantly enhance the capacity of these cells to process and present antigens to T cells [17,[22][23][24]. Thus, alterations in the ratio of expression of activating/inhibitory FccR could impair the capacity of DC to prime antigen-specific T cells in a regulated manner [25,26].…”

Section: Introductionmentioning

confidence: 98%

Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

et al. 2008

View full text Add to dashboard Cite

The molecular bases responsible for the loss of T cell tolerance to myelin antigens leading to the onset of multiple sclerosis remain obscure. It has been shown that balanced signaling through activating and inhibitory receptors is critical for the maintenance of tolerance to self antigens in autoimmune disorders. However, although FccR have been shown to influence experimental autoimmune encephalomyelitis (EAE) development, their role during pathogenesis remains controversial. Here we have evaluated whether relative expression of activating (FccRIII) and inhibitory (FccRIIb) FccR can modulate myelin-specific T cell response, as well as the susceptibility to develop EAE in mice. While FccRIIb -/-mice showed a significant increase in EAE severity, an FccRIII deficiency protected mice from disease. In addition, FccRIIb -/-mice showed enhanced activation of myelin-specific effector T cells, which were significantly more effective at causing EAE in adoptive transfer experiments than were T cells from wild-type mice. In contrast, FccRIII -/-mice showed a significantly reduced activation of myelin-specific T cells and these cells failed to adoptively transfer EAE. Consistently, increased expansion of regulatory T cells (Treg) during EAE was observed only for FccRIII -/-mice, which were able to suppress disease when adoptively transferred to recipient mice. These findings suggest that the balance between activating and inhibitory FccR signaling can contribute to the maintenance of T cell tolerance to myelin antigens and modulate EAE progression.

show abstract

Section: Introductionmentioning

confidence: 98%

Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

et al. 2008

View full text Add to dashboard Cite

show abstract

“…An additional central mechanism to maintaining self-tolerance is the production of regulatory T cells (Tregs), called natural T regs. Interestingly, high affi nity interactions between the TCR and self-pMHC have been shown to promote the generation and expansion of Tregs (Bettini and Vignali;Iruretagoyena, Wiesendanger et al 2006). …”

Section: Modulation Of Central Tolerance During Adaptive Immunity By mentioning

confidence: 99%

“…Example of these type of receptors are FcγRs, which recognize the Fc-fragment of IgG antibodies and consist of one inhibitory (FCRγIIB) and either three or four different activating receptors in mice (FcγRI, III, IV) and humans (FcγRIA, IIA, IIIA and IIIB on neutrophils respectively). While the activating receptors signal through immunoreceptor tyrosine-based activating motifs or ITAM, inhibitory receptors do so through tyrosine-based inhibitory motifs or ITIM (Kalergis 2003;Iruretagoyena, Wiesendanger et al 2006;Herrada, Contreras et al 2007). Noteworthy, selective engagement of activating Fcγ receptors in bone-marrow DCs derived from FcγRIIB -/-mice results in enhanced DC maturation and induces tumor immunity (Kalergis and Ravetch 2002).…”

Section: Molecular Interactions At the Dc-t Cell Interface That Contrmentioning

confidence: 99%

“…In addition, DC-T cell synapses can be stabilized by co-stimulatory molecules on the surface of DCs and cytokines secreted by these cells in response to PAMP stimulation (Figure 2). Therefore, environments enriched in infl ammatory signals would favor the formation of stableactivating synapses over kinapses that could contribute to the activation of T cells upon encountering low avidity ligands, such as self-pMHC (Iruretagoyena, Wiesendanger et al 2006). This process is likely to favor the onset of an autoimmune response in susceptible individuals (Figure 2).…”

Section: Immunological Synapse: a Macromolecular Machine Controlling mentioning

confidence: 99%

“…TCR recognition by a cognate pMHC ligand leads to T cell activation with subsequent T cell proliferation and differentiation (Carreno, Gonzalez et al 2006;Iruretagoyena, Wiesendanger et al 2006). After TCR engagement, the Srcfamily tyrosine-kinases lck and fyn are recruited to the cell membrane to catalyze the phosphorilation of CD3ξ molecules in the tyrosine-based activating motifs (ITAM) (Gonzalez, Carreno et al 2007).…”

Section: T Cell Activation In Effector Immunological Synapsesmentioning

confidence: 99%

See 2 more Smart Citations

Contribution of dendritic cell/T cell interactions to triggering and maintaining autoimmunity

2011

View full text Add to dashboard Cite

Under healthy conditions, there is a balance between tolerance to self-tissue constituents and immunity against foreign antigens. Autoimmunity diseases (AD) take place when that equilibrium is disrupted and the immune response is directed to self-antigens, leading to injury or destruction of host tissues. The mechanisms conducing to the loss of immune tolerance remain largely unknown. The recent appearance of biological therapies has contributed to signifi cant reduction in morbidity. However, currently available therapies are associated with important side effects and work only as palliative treatments. Dendritic cells (DCs) have emerged as key players in developing and maintaining adaptive immunity due to their capacity to prime and modulate T cell function. Therefore, because DCs work as central modulators of immune tolerance, it is likely that alterations in their function can lead to the onset of autoimmune-infl ammatory diseases. By modulating DC function, novel pathways in antigen-specifi c tolerance could be established. In this article, the possible contribution of altered DC-T cell interactions to the onset of autoimmunity are discussed. In addition, we expand on the notion that some of the functions of these cells could be relevant targets for intervening therapies aimed to restore the balance or even prevent the loss of tolerance.

show abstract

Induction of Tolerogenic Dendritic Cells by NF-κB Blockade and Fcγ Receptor Modulation

Carreño

Riedel

Kalergis

2010

Methods in Molecular Biology

View full text Add to dashboard Cite

Autoimmune diseases develop as a result of an unbalanced adaptive immunity that targets self-antigens and causes destruction of healthy host tissues. Maintenance of peripheral immune tolerance to self- antigens is mainly mediated by dendritic cells (DCs), professional antigen-presenting cells that modulate the activation of T cells. Due to their key role as regulators of adaptive immunity, identification of means of enhancing DC tolerogenic capacity and therapeutic potential is a priority goal to reduce autoimmune disease burden in an antigen-specific manner. Our findings suggest novel approaches to enhance DC capacity to induce self-tolerance and reduce the severity of autoimmune disorders. Specifically, we have shown, both in vitro and in vivo, that NF-κB blockade on DCs by andrographolide or rosiglitazone can significantly enhance the tolerogenic capacity of DCs. Furthermore, we have observed that expression ratio of the activating FcγRIII or the inhibitory FcγRIIb is determinant for the tolerogenic potential of DCs. In this chapter, we describe the procedures to produce tolerogenic DCs and explain the potential therapeutic use of two NF-κB inhibitors for the treatment of autoimmune disease models, such as experimental autoimmune encephalomyelitis (EAE) and systemic lupus erythematosus (SLE) in mice. Therefore, our studies support the notion that FcγRs and NF-κB can be considered as pharmacological targets to increase the capacity of DCs to induce or restore self-tolerance and decrease inflammatory damage to self-tissues.

show abstract

The Dendritic Cell-T Cell Synapse as a Determinant of Autoimmune Pathogenesis

Cited by 28 publications

References 173 publications

Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

Activating and inhibitory Fcγ receptors can differentially modulate T cell‐mediated autoimmunity

Contribution of dendritic cell/T cell interactions to triggering and maintaining autoimmunity

Induction of Tolerogenic Dendritic Cells by NF-κB Blockade and Fcγ Receptor Modulation

Contact Info

Product

Resources

About