1. INTRODUCTION
For decades, the central nervous system (CNS) has been considered an immune-isolated organ, due to the lack of lymphatic vessels and the restriction of the blood-brain barrier (BBB), which limits the access of immune cells (Arcuri, Mecca, Giambanco & Donato, 2019; Mapunda, Tibar, Regragui & Engelhardt, 2022). However, recent studies have shown evidence of the presence of immune cells in both physiological and pathological conditions within the CNS (Arcuri, Mecca, Giambanco & Donato, 2019; Stephenson, Nutma, van der Valk & Amor, 2018). The use of lymphatic-cell-reporter mice has demonstrated the existence of classic lymphatic vessels within the layers of the meninges and the presence of adaptive immune cells, such as T and B lymphocytes, in these vessels under homeostatic conditions (Buckley & McGavern, 2022; Louveau et al., 2015).
The meninges protect the brain and spinal cord and consist of three different layers. The outermost layer, the dura mater, is a collagenous membrane that is richly vascularized and innervated, and contains numerous lymphatic vessels (Mapunda, Tibar, Regragui & Engelhardt, 2022; Rua & McGavern, 2018). The middle layer, the arachnoid mater, primarily regulates molecules transport (Yasuda et al., 2013) and the innermost layer, the pia mater, surrounds the parenchyma of the CNS. Together, the arachnoid and pia maters are referred to as the leptomeninges (Decimo, Fumagalli, Berton, Krampera & Bifari, 2012). Between these two lies the subarachnoid space (SAS), composed of trabeculae and collagen fibers. The cerebrospinal fluid (CSF), produced by the ependymal cells of the choroid plexus (CP), flows through this space (Rua & McGavern, 2018). The dural lymphatic vessels reabsorb the CSF from the SAS through glymphatic system (Buckley & McGavern, 2022; Prinz & Priller, 2017) (Figure 1).
Dysregulation of the CNS immune response can lead to the development of autoimmune diseases, such as multiple sclerosis (MS) (Ransohoff, 2016). A thorough comprehension of the role of T cells in this scenario, as well as the molecular processes underlying age-related changes under normal conditions, could provide new opportunities for research on understanding the brain in autoimmune and neurodegenerative diseases.