Brain regulatory T cells suppress astrogliosis and potentiate neurological recovery

• Published in: Nature (London) Vol. 565; no. 7738; pp. 246 - 250
• Main Authors: Ito, Minako, Komai, Kyoko, Mise-Omata, Setsuko, Iizuka-Koga, Mana, Noguchi, Yoshiko, Kondo, Taisuke, Sakai, Ryota, Matsuo, Kazuhiko, Nakayama, Takashi, Yoshie, Osamu, Nakatsukasa, Hiroko, Chikuma, Shunsuke, Shichita, Takashi, Yoshimura, Akihiko
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.01.2019; Nature Publishing Group
• Subjects: 13/31; 13/51; 38/61; 631/250/1619/554/1898/1271; 631/250/371; Adipose tissue; Amphiregulin; Animals; Astrocytes; Astrocytes - pathology; Brain; Brain - cytology; Brain - immunology; Brain injuries; Brain injury; Brain Ischemia - immunology; Brain Ischemia - pathology; CCL20 protein; Cell Movement; Cell Proliferation; Chemokine CCL1 - immunology; Chemokine CCL20 - immunology; Chemokines; Cytokines; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; Foxp3 protein; Gene expression; Genes; Gliosis; Gliosis - pathology; Growth factors; Head injuries; Health aspects; Homeostasis; Humanities and Social Sciences; Immunological tolerance; Immunoregulation; Infiltration; Inflammation; Interleukin-2 - immunology; Interleukin-33 - immunology; Interleukin-6 - immunology; Interleukins; Ischemia; Kinases; Letter; Lymphocytes; Lymphocytes T; Male; Mice; Mice, Inbred C57BL; multidisciplinary; Nervous system; Nervous system diseases; Neurological complications; Neurons; Neuroprotection - immunology; Neurotoxicity; Phenols (Class of compounds); Receptors, Antigen, T-Cell - immunology; Receptors, CCR - metabolism; Receptors, Serotonin - genetics; Receptors, Serotonin - metabolism; Recovery; Recovery (Medical); Rehabilitation; Science; Science (multidisciplinary); Serotonin; Serotonin - metabolism; Serotonin receptors; Serotonin S7 receptors; Signal Transduction; Spinal cord injuries; STAT3 Transcription Factor - metabolism; Stroke; T cell receptors; T cells; T-Lymphocytes, Regulatory - cytology; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Traumatic brain injury
• ISSN: 0028-0836; 1476-4687
• DOI: 10.1038/s41586-018-0824-5

In addition to maintaining immune tolerance, FOXP3 + regulatory T (T reg ) cells perform specialized functions in tissue homeostasis and remodelling 1 , 2 . However, the characteristics and functions of brain T reg cells are not well understood because there is a low number of T reg cells in the brain under normal conditions. Here we show that there is massive accumulation of T reg cells in the mouse brain after ischaemic stroke, and this potentiates neurological recovery during the chronic phase of ischaemic brain injury. Although brain T reg cells are similar to T reg cells in other tissues such as visceral adipose tissue and muscle 3 – 5 , they are apparently distinct and express unique genes related to the nervous system including Htr7 , which encodes the serotonin receptor 5-HT 7 . The amplification of brain T reg 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 T reg 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 T reg cells and their products may provide therapeutic opportunities for neuronal protection against stroke and neuroinflammatory diseases. In a mouse model of ischaemic stroke, regulatory T cells infiltrate the injured brain in response to the chemokines CCL1 and CCL20 and suppress excessive astrogliosis via the production of amphiregulin.