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Investigating the mechanism and role of the steady-state CXCR3-CXCL10 gut-microbiota-brain T cell axis

Award Number: F31NS130957
ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 12/19/2023
PERIOD OF PERFORMANCE END DATE: 10/18/2025

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Investigating the mechanism and role of the steady-state CXCR3-CXCL10 gut-microbiota-brain T cell axis - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2025 ( Subtotal = $44,740 )
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	2	3/26/2025	NON-COMPETING CONTINUATION	$44,270
2025	2025	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	2	8/14/2025	NON-COMPETING CONTINUATION	$470
														Subtotal = $44,740

Issue Date FY: 2024 ( Subtotal = $48,974 )
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	001	1	12/19/2023	NEW	$0
2024	2024	YALE UNIVERSITY	105 WALL ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	000	1	12/19/2023	NEW	$47,694
2024	2024	YALE UNIV	150 MUNSON ST	NEW HAVEN	CT	06511	SOUTH CENTRAL CT	USA	Extramural Research Programs in the Neurosciences and Neurological Disorders	002	1	5/17/2024	NEW	$1,280
														Subtotal = $48,974

Grand Total All Awards = $93,714

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Investigating the mechanism and role of the steady-state CXCR3-CXCL10 gut-microbiota-brain T cell axis

Award Number: F31NS130957

ORGANIZATION: NATIONAL INSTITUTE OF NEUROLOGICAL DISORDERS AND STROKE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 12/19/2023

PERIOD OF PERFORMANCE END DATE: 10/18/2025

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