New Discovery: Immune Cells Live in The Healthy Brain and Keep The Mind in Balance

Researchers have discovered that certain T cells, which are important for the body’s defense, also live permanently inside the brain, something that was previously thought not to be the case. These cells help keep the brain healthy, communicate with other brain cells, and their presence is linked to the balance between the gut, body fat, and brain. This discovery could open new avenues for understanding neurological diseases and how the immune system protects the brain.

T cells are a type of immune system cell that plays a central role in defending the body against infection and disease. They are part of what is called “adaptive immunity,” which is the part of the immune system that learns to recognize and remember specific invaders, such as viruses and bacteria. There are different types of T cells, but in general, they help coordinate the immune response and destroy infected cells.

T cells play a key role in treating cancer, especially through so-called immune therapies. They have the ability to recognize and destroy tumor cells, which has been explored in approaches such as CAR-T cell therapy, in which a patient’s own T cells are modified in the laboratory to attack cancer cells more effectively.

These therapies have shown promising results, especially in certain types of leukemia and lymphoma, and are continually being refined to treat other types of solid cancers.

T cell (red) attacking cancer cell (blue).

Until recently, it was believed that T cells did not live inside the brain, but merely protected it from surrounding structures, such as the meninges.

A new study, conducted by researchers at Yale School of Medicine, USA, and published in Nature, has revealed that some CD4 T cells, called "αβ T cells", actually live inside the brain, more specifically in a region called the subfornical organ (SFO), in both mice and humans.

This is an important discovery because until now it was thought that the brain did not permanently house cells of the adaptive immune system. These T cells in the brain are different from those found in the meninges, which are the membranes surrounding the brain. They are not found in blood vessels, but rather within the brain tissue itself.

In addition, they have a unique behavior: they produce a substance called interferon gamma (IFNγ), which helps maintain the balance and proper functioning of the central nervous system. They also express special proteins, such as CXCR6, which help these cells to attach themselves to the brain.

Surprisingly, these T cells that live in the brain are “primed” in other parts of the body, such as the gut and adipose tissue (fat). The study showed that the gut microbiome (the bacteria that live in our intestines) and body fat directly influence the presence of these T cells in the brain. They travel from these locations to the brain, where they settle in the subfornical organ.

This discovery shows that there is a constant communication between the immune system, the brain, the gut and body fat. T cells in the brain help to maintain its stability and proper functioning, something known as homeostasis.

If there are changes in the gut microbiome or the composition of body fat, this could affect the number of these cells in the brain, and potentially, overall mental and neurological health.

In summary, the study revealed that the brain has its own resident T cells, distinct from the cells in the meninges, and that they play an active role in maintaining brain health. This connection between the immune system, the gut, fat and the brain opens new doors to understanding neurological diseases and the impact of overall body health on the brain.

READ MORE:

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

Nature (2025). 28 May 2025

https://doi.org/10.1038/s41586-025-09050-7

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 unclear2,3,4. 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.