The central nervous system (CNS) and the circulating cells of the immune system are engaged in a dialogue, which occurs within the borders of the brain outside the parenchyma. The beneficial role of the immune system in brain recovery after injury has been demonstrated. In particular, T cells are required for the recruitment of blood-borne monocyte-derived macrophages from the periphery to the cerebrospinal fluid through the choroid plexi and meninges upon brain insult. The recruited macrophages are required to terminate the local neurotoxic inflammatory response of activated resident native macrophages of the CNS parenchyma such as microglia. Therefore, T cells support normal brain function, neuroprotection and regeneration by regulating the balance between the need and the risk of autoimmune response.
According to the concept of protective autoimmunity, age-related brain dysfunction correlates with age-related immune compromise in regards to hippocampus-dependent memory deterioration. Therefore, the loss of cognitive function in aging can be associated with the aging of the immune system. It has been shown that regulatory T cells (Tregs) reside at the borders of the CNS, recognize specific brain antigens and contribute to hippocampus-dependent cognitive function. However, their specific role regarding the impact on cognitive function during the process of brain aging has not yet been investigated as well as their interaction with other effector T cells.
We plan to investigate the role of Tregs in regards to loss of hippocampal cognitive function in brain aging by using specific DT-DEREG mice allowing to achieve 90% depletion of Tregs in aged versus young control mice. We will characterize those mice behaviourally by their performance of the Morris water maze task and functionally by biochemical (FACS, Elisa, qRT-PCR) and histological (IHC, IF) tests in order to study the mechanism of Tregs activity (cytokine balance, suppressive activity on effector T cells) and their localization in the borders of the CNS versus peripheral immune organs. Moreover, we plan to explore the antigen specificity of Tregs by performing T cell receptor deep sequencing with the final aim to identify specific antigens bound by Tregs in aged mice.
If the relevant role of Tregs in brain aging can be confirmed, this could suggest pharmacological strategies, which would target T cell activity by T cell-based vaccination against specific antigens in order to prevent loss of cognitive function and memory in young adults that are immunodeficient and/or to delay it in elderly.