TLR-4 ligation of dendritic cells is sufficient to drive pathogenic T cell function in experimental autoimmune encephalomyelitis.

Abstract

BACKGROUND:

Experimental autoimmune encephalomyelitis (EAE) depends on the initial activation of CD4(+) T cells responsive to myelin autoantigens. The key antigen presenting cell (APC) population that drives the activation of naïve T cells most efficiently is the dendritic cell (DC). As such, we should be able to trigger EAE by transfer of DC that can present the relevant autoantigen(s). Despite some sporadic reports, however, models of DC-driven EAE have not been widely adopted. We sought to test the feasibility of this approach and whether activation of the DC by toll-like receptor (TLR)-4 ligation was a sufficient stimulus to drive EAE.

FINDINGS:

Host mice were seeded with myelin basic protein (MBP)-reactive CD4+ T cells and then were injected with DC that could present the relevant MBP peptide which had been exposed to lipopolysaccharide as a TLR-4 agonist. We found that this approach induced robust clinical signs of EAE.

CONCLUSIONS:

DC are sufficient as APC to effectively drive the differentiation of naïve myelin-responsive T cells into autoaggressive effector T cells. TLR-4-stimulation can activate the DC sufficiently to deliver the signals required to drive the pathogenic function of the T cell. These models will allow the dissection of the molecular requirements of the initial DC-T cell interaction in the lymphoid organs that ultimately leads to autoimmune pathology in the central nervous system.

• Authors: Richard J Mellanby, Helen Cambrook, Darryl G Turner, Richard A O'Connor, Melanie D Leech, Florian C Kurschus, Andrew S MacDonald, Bernd Arnold, Stephen M Anderton
• Journal: Journal of neuroinflammation (J Neuroinflammation) Vol. 9 Pg. 248 (Oct 30 2012) ISSN: 1742-2094 [Electronic] England
• PMID: 23111144 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Cytokines
• Histocompatibility Antigens Class II
• Lipopolysaccharides
• Myelin Basic Protein
• Peptide Fragments
• Toll-Like Receptor 4
• Freund's Adjuvant

Topics

• Animals
• Antigen-Presenting Cells
• Cell Differentiation (drug effects)
• Cytokines (metabolism)
• Dendritic Cells (drug effects, metabolism)
• Disease Models, Animal
• Encephalomyelitis, Autoimmune, Experimental (chemically induced, pathology)
• Freund's Adjuvant (adverse effects)
• Histocompatibility Antigens Class II (metabolism)
• Ligation
• Lipopolysaccharides (toxicity)
• Lymphocyte Activation (drug effects)
• Mice
• Myelin Basic Protein (metabolism, pharmacology)
• Peptide Fragments (pharmacology)
• T-Lymphocytes (drug effects, immunology, metabolism, pathology)
• Toll-Like Receptor 4 (immunology, metabolism)