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).