Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery.

Ito M, Komai K, Mise-Omata S, Iizuka-Koga M, Noguchi Y, Kondo T, Sakai R, Matsuo K, Nakayama T, Yoshie O, Nakatsukasa H, Chikuma S, Shichita T, Yoshimura A.
Source: Nature
Publication Date: (2019)
Issue: 565 (7738): 246-250
Research Area:
Immunotherapy / Hematology
Gene Expression
Cells used in publication:
T cell, mouse - C57BL/6
Species: mouse
Tissue Origin: blood
T cell, mouse, stim
Species: mouse
Tissue Origin: blood
4D-Nucleofector™ X-Unit

For nucleofection, mouse Treg cells (1.5 × 106 per well) were isolated from spleen and lymph nodes and mixed with 20 µl primary cell nucleofection solution (P4 Primary Cell 4D-Nucleofector X kit S; 32 RCT, V4XP-4032; Lonza). Cells were then incubated with 15 µl RNP complex, transferred to Nucleofection cuvette strips (4D-Nucleofector X kit S; Lonza), and electroporated using a 4D nucleofector (Lonza) with a DS158 pulse. After nucleofection, transfected cells were transferred to 96-well plates with pre-warmed 200 µl complete T cell medium and cultured for 1 h. After resting culture, Treg cells (1 × 106 cells per body) were transferred intravenously into post-ischaemic Cd3e-/- mice on day 5 after stroke onset, and analysed on day 14.


In addition to maintaining immune tolerance, FOXP3+ regulatory T (Treg) cells perform specialized functions in tissue homeostasis and remodelling1,2. However, the characteristics and functions of brain Treg cells are not well understood because there is a low number of Treg cells in the brain under normal conditions. Here we show that there is massive accumulation of Treg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain Treg cells are similar to Treg cells in other tissues such as visceral adipose tissue and muscle3-5, they are apparently distinct and express unique genes related to the nervous system including Htr7, which encodes the serotonin receptor 5-HT7. The amplification of brain Treg cells is dependent on interleukin (IL)-2, IL-33, serotonin and T cell receptor recognition, and infiltration into the brain is driven by the chemokines CCL1 and CCL20. Brain Treg cells suppress neurotoxic astrogliosis by producing amphiregulin, a low-affinity epidermal growth factor receptor (EGFR) ligand. Stroke is a leading cause of neurological disability, and there are currently few effective recovery methods other than rehabilitation during the chronic phase. Our findings suggest that Treg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases.