The subfornical organ is a nucleus for gut-derived T cells that regulate behaviour

Tomomi M. Yoshida, Mytien Nguyen, Le Zhang, Benjamin Y. Lu, Biqing Zhu, Katie N. Murray, Yann S. Mineur, Cuiling Zhang, Di Xu, Elizabeth Lin, Joseph Luchsinger, Sagar Bhatta, Daniel A. Waizman, Mackenzie E. Coden, Yifan Ma, Kavita Israni-Winger, Anthony Russo, Haowei Wang, Wenzhi Song, Jafar Al Souz, Hongyu Zhao, Joseph E. Craft, Marina R. Picciotto, Jaime Grutzendler, Marcello Distasio, Noah W. Palm, David A. Hafler () and Andrew Wang ()
Additional contact information
Tomomi M. Yoshida: Yale School of Medicine
Mytien Nguyen: Yale School of Medicine
Le Zhang: Yale School of Medicine
Benjamin Y. Lu: Yale School of Medicine
Biqing Zhu: Yale University
Katie N. Murray: Yale School of Medicine
Yann S. Mineur: Yale School of Medicine
Cuiling Zhang: Yale School of Medicine
Di Xu: Yale School of Medicine
Elizabeth Lin: Yale School of Medicine
Joseph Luchsinger: Yale School of Medicine
Sagar Bhatta: Yale School of Medicine
Daniel A. Waizman: Yale School of Medicine
Mackenzie E. Coden: Yale School of Medicine
Yifan Ma: Yale School of Medicine
Kavita Israni-Winger: Yale School of Medicine
Anthony Russo: Yale School of Medicine
Haowei Wang: Yale School of Medicine
Wenzhi Song: Yale School of Medicine
Jafar Al Souz: Yale School of Medicine
Hongyu Zhao: Yale University
Joseph E. Craft: Yale School of Medicine
Marina R. Picciotto: Yale School of Medicine
Jaime Grutzendler: Yale School of Medicine
Marcello Distasio: Yale School of Medicine
Noah W. Palm: Yale School of Medicine
David A. Hafler: Yale School of Medicine
Andrew Wang: Yale School of Medicine

Nature, 2025, vol. 643, issue 8071, 499-508

Abstract: Abstract Specialized immune cells that reside in tissues orchestrate diverse biological functions by communicating with parenchymal cells1. The contribution of the innate immune compartment in the meninges and the central nervous system (CNS) is well-characterized; however, whether cells of the adaptive immune system reside in the brain and are involved in maintaining homeostasis is unclear2–4. Here we show that the subfornical organ (SFO) of the brain is a nucleus for parenchymal αβ T cells in the steady-state brain in both mice and humans. Using unbiased transcriptomics, we show that these extravascular T cells in the brain are distinct from meningeal T cells: they secrete IFNγ robustly and express tissue-residence proteins such as CXCR6, which are required for their retention in the brain and for normal adaptive behaviour. These T cells are primed in the periphery by the microbiome, and traffic from the white adipose and gastrointestinal tissues to the brain. Once established, their numbers can be modulated by alterations to either the gut microbiota or the composition of adipose tissue. In summary, we find that CD4 T cells reside in the brain at steady state and are anatomically concentrated in the SFO in mice and humans; that they are transcriptionally and functionally distinct from meningeal T cells; and that they secrete IFNγ to maintain CNS homeostasis through homeostatic fat–brain and gut–brain axes.

Date: 2025
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DOI: 10.1038/s41586-025-09050-7

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