Studying the Interactions of Cytotoxic T Cells with Neurons in vivo
Mario Kreutzfeldt
Doctoral thesis
Date of Examination:
2013-03-12
Date of issue:
2013-12-13
Advisor:
Brück, Wolfgang Prof. Dr.
Referee:
Wienands, Jürgen Prof. Dr.
Referee:
Simons, Mikael Prof. Dr.
Persistent Address: http://hdl.handle.net/11858/00-1735-0000-0022-6094-8
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Abstract
English
The central nervous system (CNS) is considered as largely isolated from the immune system – a status referred to as “immune privilege”. But CNS-tissue is constantly surveyed by immune cells and can under certain circumstances, such as viral infections, become a target of inflammatory responses. Cytotoxic T cells (CTLs) combat viruses in peripheral organs as well as the CNS and can contribute to inflammation-induced tissue damage. This concept drives the viral déjà vu mouse model, where defined sequences of lymphocytic choriomeningitis virus (LCMV) infections cause severe CNS inflammation. The CTL response targets viral epitopes of persistently infected neurons that are shared by the used viruses. To better understand the requirements and consequences for CTL:neuron interactions in vivo, different epitope mutants of the immunodominant LCMV epitopes NP396-404 and GP33-41 with different affinities to MHC class I were tested for their contribution in déjà vu disease. While the CTL response against the LCMV nucleoprotein epitope NP396-404 was shown to be pivotal for viral déjà vu disease, the co-expression of high affinity GP33 mutant epitopes did indeed aggravate disease but could not induce viral déjà vu disease in the absence of NP396-404. Furthermore, the molecular mediators and structural consequences of CTL attack on neurons were investigated by using bone marrow chimeras of CTL effector molecules and their receptors. CTL-derived Interferon-γ (IFN-γ) was identified as key mediator of CTL-induced synapse loss (“deafferentation”) in virus-infected neurons. Deafferentation was found to correlate with clinical disability and dependend on the activation of the JAK–STAT1 pathway by IFN-γ-receptor signaling in target neurons. A similar IFN-γ signature was found in human neurons affected by Rasmussen’s encephalitis, a CTL-mediated autoimmune disease. These results provide important insights into the molecular mechanisms operating at the immunological synapse between CTL and neuron in inflammatory diseases of the CNS.
Keywords: CTL; CNS; CD8; LCMV; Rasmussen; Encephalitis; MHCI
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Molekulare Medizin [169]