Exploring the Role and Mechanisms of Resident T Cell Populations in Neurogenesis
Annalise Bracher1, Megan Donnay2, Kaila Gemenes2, Joanna Halkias3, Madeline Andrews 2
1University of Arizona College of Medicine Phoenix, 2Arizona State University: School of Biological and Health Systems Engineering, 3University of California, San Francisco School of Medicine
Objective:
To investigate the role and mechanisms of brain resident T cells in neurodevelopmental dynamics.
Background:
The development of the human cortex is an intricately governed process involving the coordination of molecular mechanisms across multiple cell types. Improper regulation of this development can lead to neurological disorders such as epilepsy and Autism Spectrum Disorder. As mediators of neuroinflammatory states, T cells are prominently involved in neurological disease. While the brain parenchyma was previously viewed as a site of immune privilege, a growing body of evidence indicates that resident memory CD8+ and CD4+ T cells exist in the healthy postnatal and adult brains of mice and humans. However, many details regarding their function within the developing brain remain unknown.
Design/Methods:
We investigated primary neural tissue for the presence of CD3+CD4+ T cells using in situ hybridization and immunohistochemistry. Naïve and memory T cells were isolated by fluorescence activated cell sorting and co-cultured in human stem cell-derived forebrain organoids at peak neurogenesis (week 5) to assess T cell-induced neural cell population changes via immunohistochemistry and confocal microscopy.
Results:
We have identified the presence of CD3+CD4+ T cells, with subpopulations of naïve and memory types, in the progenitor zone of primary human neural tissue. Additionally, organoids co-cultured with memory T cells show reduction in neural cell death compared to control organoids. Closer inspection of progenitor populations reveal an increase in intermediate progenitor cells (IPC), the neurogenic transit amplifying progenitors that are expanded in the human brain and give rise to increased numbers of neurons.
Conclusions:
These findings support a T cell-influenced neurogenic expansion via IPCs with implications for cortical expansion and temporal dynamics of the developing human brain. While additional investigation is required to fully elucidate the mechanisms behind these changes, these results are a first step in understanding the role of T cells within proper neurodevelopment.