Investigating T cells in the context of Neuroimmunology: Molecular and cellular mechanisms during a stress response and a patient-based study in Parkinson's disease

For a long time, the nervous system and the immune system have been studied as isolated entities, but a growing body of evidence shows that there is an extensive crosstalk between both systems. In fact, neurons and immune cells share certain functional features and reside in close proximity within the tissues, enabling them to effectively communicate. T cells are crucial for mounting and controlling almost any kind of immune response. However, when dysregulated, T cells fail to protect the host from invading pathogens or can cause damage to surrounding tissues, leading to autoimmunity-related pathology. In the first part of this cumulative thesis, we aimed at identifying novel genes regulating CD4 T cell responses and identified VIMP, one of the 25 human proteins containing the 21st amino acid selenocysteine, as a gene having anti-inflammatory functions. Furthermore, T cells express various neurotransmitter receptors allowing the integration of neuronal signal for an appropriate response. In the second part, we showed a CD4-T-cell-intrinsic mechanism through which stress hormones mediate their control over the immune system. We identified a previously unrecognized pathway regulating CD4 T cell differentiation that involves the circadian clock gene Per1 and mTORC1 signalling. Finaly, T cells involvement in different neuropathologies has been reported in the past few decades. Emerging evidence indicates the involvement of the immune system and in particular T cells in the pathogenesis of Parkinson’s disease (PD), the 2nd most common neurodegenerative disease. In the 3rd part of the thesis we systematically characterized the immunological status of early-to-mid stage PD patients and matched healthy controls, and identified a distinct peripheral immunological fingerprint in PD patients, especially in the CD8 T-cell compartment. The findings of the studies described in this cumulative thesis advance our understanding of the regulatory nodes of CD4 T cells during a stress response and fill the knowledge gap on the early involvement of CD8 T cells and other immune subsets in neurodegenerative diseases in the case of PD.