Abstract
Multiple sclerosis is a chronic, disseminated inflammation of the central nervous system which is thought to be driven by autoimmune T cells. Genetic association studies in multiple sclerosis and a large number of studies in the animal model of the disease support a role for effector/memory T helper cells. However, the mechanisms underlying relapses, remission and chronic progression in multiple sclerosis or the animal model experimental autoimmune encephalomyelitis, are not clear. In particular, there is only scarce information on the role of central nervous system-invading naive T helper cells in these processes. By applying two-photon laser scanning microscopy we could show in vivo that antigen unexperienced T helper cells migrated into the deep parenchyma of the inflamed central nervous system in experimental autoimmune encephalomyelitis, independent of their antigen specificity. Using flow cytometric analyses of central nervous system-derived lymphocytes we found that only antigen-specific, formerly naive T helper cells became activated during inflammation of the central nervous system encountering their corresponding antigen.
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Abbreviations
- APCs:
-
Antigen presenting cells
- BBB:
-
Blood-brain barrier
- CCL-21:
-
CC-chemokine ligand 21
- CNS:
-
Central nervous system
- EAE:
-
Experimental autoimmune encephalomyelitis
- ICAM-1:
-
Intercellular adhesion molecule 1
- IL:
-
Interleukin
- INF:
-
Interferon
- i.v.:
-
Intravenous
- LFA-1:
-
Leukocyte function-associated antigen 1
- MACS:
-
Magnetic cell sorting
- MOG:
-
Myelin oligodendroycte glycoprotein35-55
- MS:
-
Multiple sclerosis
- OVA:
-
Ovalbumin323-339
- PLP:
-
Proteolipid protein
- Rag 1-/-:
-
B6.129S7-Rag1tm1Mom/J mice
- TH cell:
-
T helper cell
- TPLSM:
-
Two-photon laser scanning microscopy
- VCAM:
-
Vascular cell adhesion molecule
- VLA-4:
-
Very late antigen-4
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Acknowledgments
This study has been supported by the German Research Foundation (DFG, SFB-TR 128/B9 to VS and FZ).
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We thank Heike Ehrengard and Christin Liefländer for technical assistance and Cheryl Ernest for proofreading the manuscript.
SF was responsible for executing the research project and writing the manuscript, performing all experiments, preparing the figures and the statistical analysis. EW assisted in data analysis and writing and editing the manuscript. JB assisted technically with research. MP assisted with data analysis. VS contributed to the design of the experiments and assisted with data analysis. FZ assisted in editing the manuscript. VS and FZ directed all aspects of this research project including the experimental design.
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The authors declare no conflict of interest.
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Volker Siffrin and Esther Witsch are joint senior authors.
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Franck, S., Paterka, M., Birkenstock, J. et al. Phenotype of Antigen Unexperienced TH Cells in the Inflamed Central Nervous System in Experimental Autoimmune Encephalomyelitis. J Neuroimmune Pharmacol 12, 305–313 (2017). https://doi.org/10.1007/s11481-016-9718-1
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DOI: https://doi.org/10.1007/s11481-016-9718-1