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The role of Tregs at the choroid plexus in terms of brain maintenance and plasticity

Applicant Graubardt Nadine
Number 142150
Funding scheme Fellowships for prospective researchers
Research institution
Institution of higher education Institution abroad - IACH
Main discipline Immunology, Immunopathology
Start/End 01.04.2012 - 31.03.2013
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All Disciplines (4)

Discipline
Immunology, Immunopathology
Cellular Biology, Cytology
Molecular Biology
Neurophysiology and Brain Research

Keywords (4)

Protective autoimmunity; Brain aging; Regulatory T cells; DT-DEREG mice

Lay Summary (English)

Lead
Lay summary

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.

Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Abstract

The central nervous system (CNS) was long considered as an "immune priviledged site", however this concept was challenged by recent findings demonstrating the beneficial roles of the systemic immune system in CNS protection, repair and maintenance. Thus, the concept of "protective autoimmunity" was introduced. In particular, brain parenchyma and leukocytes are involved in a cross-talk regulating the delicate equilibrium between the need and the risk of autoimmunity. T regulatory cells (Tregs) have been shown to localize at the choroid plexus and to interact with components of the CNS. Tregs have been shown to play important roles in the CNS upon injury such as the recruitment of peripheral blood-borne monocytes-derived macrophages, which terminate the immune response mediated by microglia, therefore promoting tissue recovery. However, the role of Tregs during the process of brain aging and their impact upon loss of cognitive function associated with this process need further elucidation. We aim to define the role of these cells in the context of brain aging by means of experiments based on the depletion of Tregs. In order to deplete this cell population we will use specific transgenic mice (DT-DEREG mice). The functional response of Tregs will be assessed by behavioral characterization of aged mice compared to young mice upon Tregs depletion. Biochemical and histological analysis of the borders of the CNS where Tregs are located and interact with components of the CNS will be performed. Moreover, in order to define differences in the TCR sequence of Tregs in aged and young mice, deep sequencing analysis will be carried in peripheral immune organs and in the borders of the CNS.
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