2.1. T cells and where to find them
In physiological conditions, the highest concentration of immune cells
in the CNS can be found within the dura mater. These include T and B
lymphocytes, macrophages and other myeloid cells (Buckley & McGavern,
2022; Louveau et al., 2015). T lymphocytes travel from CNS postcapillary
venules to the meninges, specifically to dura mater and the SAS (Mrdjen
et al., 2018; Ransohoff & Engelhardt, 2012). T cells exit via lymphatic
vasculature and reach the draining cervical lymph nodes (Buckley &
McGavern, 2022). Although the skull and vertebral bodies possess bone
marrow pockets (Cugurra et al., 2021), the majority of T lymphocytes in
the CNS comes from the blood (Rustenhoven et al., 2021).
The process of diapedesis requires several steps, starting with the
capture of immune cells on the endothelium by selectins, which slows
down their movement. The recognition of their G-protein coupled
receptors (GPCRs) then allows the arrest and crawling of immune cells in
an integrin-dependent manner, leading to the passage through the
endothelium (Mapunda, Tibar, Regragui & Engelhardt, 2022). T
lymphocytes diapedesis from CNS postcapillary venules is restricted to
activated memory T cells, which are capable of expressing C-C chemokine
receptor type 7 (CCR7) and recognizing C-C chemokine ligand type 19
(CCL19), which facilitates the migration of this subset of T cells
through the BBB (Marchetti & Engelhardt, 2020). Moreover, the BBB
endothelial cells constitutively express atypical chemokine receptor 1
(ACKR1), which, by transporting chemokines to the luminal side of the
venular endothelium, restricts the crossing of this barrier to activated
T cells (Marchetti et al., 2022). In steady state,
CD4+ T lymphocytes are able to cross the BBB through
leukocyte function-associated antigen-1 (LFA-1)-dependent adhesive
interactions (Castro Dias et al., 2021; Marchetti & Engelhardt, 2020).
Different types of T helper cells may use different mechanisms and sites
to perform the diapedesis process (Mundt, Greter, Flugel & Becher,
2019). For instance, T helper 17 (Th17) lymphocytes, which express CCR6
and CCR4, preferably enter via CP-associated blood-CP barrier (BCPB) by
LFA-1. On the other hand, T helper 1 (Th1) pass the BBB in the spinal
cord microvessels through VLA-4 (Glatigny, Duhen, Oukka & Bettelli,
2011; Rothhammer et al., 2011). In addition, CD8+ T
cells are more dependent on LFA-1 for diapedesis in the CNS and also
require endothelial junctional adhesion molecule B (JAM-B) to pass
through the BBB (Alvarez et al., 2015; Mapunda, Tibar, Regragui &
Engelhardt, 2022).
The repertoire of immune cells in a non-neuroinflammatory state has been
characterized by many authors. Analysis using single-cells techniques
has revealed a wide variety of immune populations, such as
border-associated macrophages (BAMs), monocytes, natural killer (NK)
cells, dendritic cells, innate lymphoid cells, B and T lymphocytes. In
the healthy CNS, T cells could be found patrolling the meninges and the
CP, but not in the brain parenchyma (Table 1) (Mundt, Greter, Flugel &
Becher, 2019; Prinz & Priller, 2017). Due to the restrictions of the
BBB, activated T cells with a memory phenotype and fewer tissue-resident
antigen-presenting cells (APCs) can be found in the dura mater, as well
as the SAS and CSF (de Graaf et al., 2011; Kawakami & Flugel, 2010;
Kivisakk, Tucky, Wei, Campbell & Ransohoff, 2006). Moreover, these T
lymphocytes upregulate genes and cytotoxicity-related markers that
resemble tissue-resident T cells (Croese, Castellani & Schwartz, 2021;
Norris & Kipnis, 2019). T cells constitute a significant portion of the
immune environment within the CSF, making up as much as 84% of the
total of immune cells. Among T cells, CD4+ cells
comprise 48.95%, CD8+ cells represent 17.61%, double
positive CD4+CD8+ cells represent
9.63%, regulatory T cells (Treg) constitute 2.49%, and natural killer
(NK) cells make up 3.45%. The ratio of CD4+ T cells
to CD8+ T cells is estimated to be around 3.1 to 1.
(Piehl et al., 2022; Ransohoff & Engelhardt, 2012). .