Date of Award

Spring 1-1-2025

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Immunobiology

First Advisor

Wang, Andrew

Abstract

Specialized immune cells residing in tissues orchestrate diverse biological functions through communication with parenchymal cells. The contribution of the innate immune compartment in the meninges and central nervous system (CNS) is well-characterized, however, whether T cells as part of the adaptive immune system reside in the brain and are involved in homeostasis is poorly understood. Here, we identify that the subfornical organ (SFO) region of the brain is a nucleus for parenchymal T cells in the steady-state brain in both mice and humans. Using unbiased transcriptomics, we found that these extravascular T cells in the mouse brain are distinct from meningeal T cells and more robustly secrete IFNγ and express tissue residence proteins, including CXCR6, which is required for their retention in the brain. These T cells are primed in the periphery by the microbiome during the weaning period and traffic from the white adipose and gastrointestinal tissues to the brain. Once established, their numbers can be modulated by either altering the gut microbiota or adipose tissue composition, such as those induced by dietary changes. In the brain, these CD4 T cell-derived IFNγ signals astrocytes to control adaptive behavior in food-deprived states. Thus, we find that CD4 T cells reside in the brain at steady state and are anatomically concentrated in the SFO in mouse and human, are transcriptionally and functionally distinct from meningeal T cells, and secrete IFNγ to maintain CNS homeostasis via a homeostatic fat-brain and gut-brain axis.

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