2.2. T cell subsets and functions in brain homeostasis
The main functions of these T lymphocytes (Table 1) are modulating the phenotype of myeloid cells, preventing the actions of pathogens that may invade the CNS and orchestrating inflammatory environment in the brain and even modify neuronal activity (Croese, Castellani & Schwartz, 2021) (Norris & Kipnis, 2019). Interleukin (IL)-4 produced by T helper 2 cells (Th2) has been shown to play a critical role in memory and learning. This was demonstrated in experiments where cognitive impairment phenotype was rescued by passive transfer of IL-4 in T cells from Il4 -/- mice (Derecki et al., 2010). Additionally, T lymphocyte-secreted interferon gamma (IFNγ) has also been shown to participate in social behaviour. The restoration of normal social behavior in Ifng -/- mice was achieved through repopulation with wild-type T cells. IFNγ directly affects receptors on inhibitory cortical interneurons, resulting in regulation of GABA production (Filiano et al., 2016). T lymphocytes also play a key role in fetal and adult neurogenesis. The transcriptional transition to mature microglia is demonstrated to be dependent of CD4+ T cells (Prinz, Masuda, Wheeler & Quintana, 2021). Further characterization of this subset showed that Th2 lymphocytes produce cytokines which activate microglia, and subsequently, induce neurogenesis and oligodendrogenesis in adult neural progenitor cells (Arcuri, Mecca, Giambanco & Donato, 2019). All this data suggests that a well-proportioned T cell population is required to maintain proper neuronal activity.
Different types of T lymphocytes could be found in the CNS during homeostatic states (Table 1). Treg cells may be present in the meninges, CP, CSF and perivascular spaces. Their process of diapedesis is determined by chemokines CCL1 and CCL20, cytokines such as IL-2 and IL-33, and serotonin. CNS Tregs upregulate exclusive genes such asHtr7 (Iellem, 2001; Ito et al., 2019). The main functions of Treg cells in the CNS are to control IFNγ and tumor necrosis factor alpha (TNFα) secretion by immune cells through their inactivation, and to moderate acute inflammation by secreting IL-10 (Liesz et al., 2009). γδ T lymphocytes can be seen in the meninges, CSF and brain parenchyma after brain injury. Two different subsets have been identified, either producing IFNγ or IL-17. After neuronal development, fetal γδ T cells persist in the meningeal spaces throughout life. These T cells mainly belong to the IL-17-producer subset. IL-17-secreting γδ T lymphocytes contribute to controlling synaptic plasticity in short-term memory tests and to encourage brain-derived neurotrophic factor (BDNF) secretion by glial cells. Moreover, IL-17 production has been linked to anxiety behaviours in mice (Alves de Lima et al., 2020; Ribeiro M, 2019). Th17 and IL-22-producing T helper cells can be found in perivascular spaces and SAS. Retinoid-related orphan receptor γt (RORγt) is differentially expressed in Th17 cells, while aryl hydrocarbon receptor (AhR) is the pivotal transcription factor of IL-22 producing cells (Sallusto et al., 2012). These subsets have a pivotal role in the initiation of inflammatory responses in the brain (Lee et al., 2022). Other immune cell types can influence T cell activity in the CNS. For example, NK cells produce IFNγ which induces the expression of TNF-related apoptosis-inducing ligand TRAIL on astrocytes. This limits autoimmune responses in the CNS by promoting T lymphocyte apoptosis (Sanmarco, Polonio, Wheeler & Quintana, 2021). Recent studies have shown that microbiota may play a role as an environmental driver in the IL-17 production by Th17 and γδ T lymphocytes in the brain (Fung, Olson & Hsiao, 2017). T cell-derived IL-17 can directly affect brain development by causing cortical malformations and distorted social behaviours, as well as cognitive dysfunction in the adult brain. On the other hand, a conserved function through evolution of IL-17 has been described since this cytokine control neuronal chemosensation in C.elegans(Norris & Kipnis, 2019).
In addition to cytokines, CD4+ T lymphocytes that produce neurotransmitters have been documented. For example, a specific subset secrets acetylcholine (ACh) to reduce the immune response and regulate blood pressure (Olofsson et al., 2016). This CD4+ T cell subset is able to sense norepinephrine, which is secreted by white adipose tissue-resident macrophages (Norris & Kipnis, 2019).