Project Summary:
The brain is an immune-privileged organ; thus, the composition and the nature of the immune response
is fundamentally different in the brain than in the periphery, where avoiding immunopathology is prioritized. Prior
studies found that human and rodent T cells isolated from brain or CSF have unique transcriptional profiles and
increased functional capability to produce cytokines such as IFN-g29. This was also confirmed in my preliminary
studies, as I found that steady-state mouse brain is enriched with CD4 T cells that highly express multiple co-
inhibitory receptors (PD-1+ LAG3+ TIGIT+) and secrete cytokines robustly upon activation (IFN-g, IL-17A).
Interestingly, this steady-state brain T cell population can be modulated by altering in the microbiota composition.
Our preliminary results reveal that gnotobiotic mice have ~2-fold fewer brain-resident T cells and significantly
fewer IFN-g and IL-17A secreting cells, and mono-colonizing gnotobiotic mice with a single species of bacteria
can partially restore this brain T cell population. The microbiome and the gut-brain axis has been demonstrated
to mediate the symptoms and progression of a wide variety of neurological disease2-7. While the role of the gut-
microbiota-T-cell-brain axis in the context of specific neurological diseases has been studied, its role at steady-
state and the mechanism of gut-educated-T cell trafficking in the steady-state brain is not known. It is essential
to understand the steady-state gut-brain T cell axis in order to fully understand the molecular mechanisms behind
neurological disease and develop better targeted therapeutics. Interestingly in our preliminary studies, we found
that the expansion of the brain-resident T cell population correlates with the massive microbiota changes
accompanying the developmentally programmed weaning reaction30 and this phenotype is absent in gnotobiotic
mice. This weaning period also happens concurrently with large neurodevelopmental changes, including peak
myelination of axons, changes in neurotransmitter and receptors, specialization of the prefrontal cortex neural
network, and thickening of cortical grey matter31. We thus hypothesize that the gut-microbiota introduced during
weaning centrally instruct microglia secrete CXCL10 to recruit CXCR3+ microbiota-educated CD4 T cells from
the periphery and establish residence in the brain to “match” brain development with the external environment.
To test this hypothesis, we propose the following aims: Aim 1 will focus on investigating how the gut commensal
microbiota composition affects brain-resident CD4 T cell plasticity in the steady-state brain. Aim 2 will focus on
studying neuroimmune interactions between CXCR3+ microbiota-educated CD4 T cells and microglia at steady-
state. Ultimately, results from this study will inform how the microbiota may play a role in optimizing the unique
steady-state T cell compartment to regulate homeostatic functions in the brain, using behavioral assays as a
readout. The applicant’s multidisciplinary mentoring team will prepare her for research independence and a
successful career as a principal investigator in neuroimmunology.
