Phenotype of Antigen Unexperienced TH Cells in the Inflamed Central Nervous System in Experimental Autoimmune Encephalomyelitis
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.
KeywordsIntravital two-photon microscopy Multiple sclerosis Experimental autoimmune encephalomyelitis Migration Naive TH cell
Antigen presenting cells
CC-chemokine ligand 21
Central nervous system
Experimental autoimmune encephalomyelitis
Intercellular adhesion molecule 1
Leukocyte function-associated antigen 1
Magnetic cell sorting
Myelin oligodendroycte glycoprotein35-55
- Rag 1-/-
- TH cell
T helper cell
Two-photon laser scanning microscopy
Vascular cell adhesion molecule
Very late antigen-4
This study has been supported by the German Research Foundation (DFG, SFB-TR 128/B9 to VS and FZ).
Compliance with Ethical Standards
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.
Conflict of Interest
The authors declare no conflict of interest.
- Brocke S, Piercy C, Steinman L, Weissman IL, Veromaa T (1999) Antibodies to CD44 and integrin alpha4, but not L-selectin, prevent central nervous system inflammation and experimental encephalomyelitis by blocking secondary leukocyte recruitment Proceedings of the National Academy of Sciences of the United States of America 96:6896-6901Google Scholar
- Kivisakk P, Imitola J, Rasmussen S, Elyaman W, Zhu B, Ransohoff RM, Khoury SJ (2009) Localizing central nervous system immune surveillance: meningeal antigen-presenting cells activate T cells during experimental autoimmune encephalomyelitis. Ann Neurol 65:457–469. doi: 10.1002/ana.21379 CrossRefPubMedPubMedCentralGoogle Scholar
- Krakowski ML, Owens T (2000) Naive T lymphocytes traffic to inflamed central nervous system, but require antigen recognition for activation European journal of immunology 30:1002-1009 doi: 10.1002/(SICI)1521-4141(200004)30:4<1002::AID-IMMU1002>3.0.CO;2-2
- Miller MJ WS, Parker I, Cahalan MD (2002) Two-photon imaging of lymphocyte motility and antigen response in intact lymph node. ScienceGoogle Scholar
- Thorsten R. Mempel SEHUHvA (2004) T-cell priming by dendritic cells in lymph nodes occurs in three distinct phases. NatureGoogle Scholar
- Wekerle H LC, Lassmann H, Meyermann R. (1986) Cellular immune reactivity within the CNS. Trends NeurosciGoogle Scholar