3.3. T cells and age-related cognitive impairment
It is well stablished that age-related systemic inflammation and a
decline in T cell function have a negative impact on cognitive function
(Lin et al., 2018). To understand the connection between inflammaging
and T cell aging in such an impenetrable system, it is important to
analyze the different factors that can influence this scenario (Figure
1).
Some studies have suggested that there may be a disruption of the
barriers that could result in the entry of immune cells into the CNS
(Banks, Reed, Logsdon, Rhea & Erickson, 2021). However, the age-related
disruption has mainly been studied in rodents, and there is still no
consensus on whether leakiness is increased over time. Studies in humans
are limited to post-mortem examinations and imaging, making it
challenging to translate the findings (Banks, Reed, Logsdon, Rhea &
Erickson, 2021). Despite the mixed evidence on passive BBB
extravasation, the systemic inflammation combined with an inherent
baseline inflammation within the CNS is known to prime the microglia and
astrocytes to adopt an altered phenotype, triggering the recruitment of
immune cells into the brain parenchyma via diapedesis (Erickson &
Banks, 2019). This is also possible by the upregulation of adhesion
molecules in the endothelium and the ependymal cells in the ventricles
and SAS, which is triggered by cytokines such as IL-1β and TNFα,
providing access to APCs and effector cells to further amplify the
inflammatory cascade.
Once in the brain parenchyma, the presence of T cells in aged
individuals has been linked to cognitive dysfunction in numerous ways.
First, a murine model of accelerated T cell senescence revealed an
increase leakage of T cells in the CNS and subsequent defects in
neurological function (Desdin-Mico et al., 2020), supporting the fact
that T cell immunosenescence is sufficient to induce this
pro-inflammatory detrimental stage. Further, the association between
age-related cognitive decay and T cell influx into the white matter was
stablished in monkeys (Batterman, Cabrera, Moore & Rosene, 2021), but
evidence in humans is still to be found.
One of the ways T cells can lead to defects in the CNS structure and
function is prompting axon degeneration in a TCR and granzyme
B-dependent manner, causing cognitive and motor impairments in the brain
of aging mice (Groh et al, 2021). The role of cytotoxic T cells in
cognitive decline is further supported by the observations of Piehl et
al (2022), which found an increased expression of C-X-C motif chemokine
receptor 6 (CXCR6) in the CD8+ T cells within the CSF
of cognitively impaired individuals, together with an accumulation of
its ligand, C-X-C motif chemokine ligand 16 (CXCL16), suggesting that
this damaging subset of T cells is being recruited in the brain.
The connection between T cell activity and loss of cognitive function
can also be seen through the presence of IFNγ-expressing
CD8+ T cells compromising neural stem cells found in
neurogenic niches of older mice (Dulken et al., 2019). Disrupting
neurogenesis, which is crucial for maintaining brain function and
plasticity, has a direct correlation with the decline in brain function
in aging organisms. Therefore, targeting this T cell population might
provide a promising therapeutic opportunity.
IL-17 has been suggested to negatively impact neurogenesis (Liu et al.,
2014), but recent evidence also suggests that it can induce neuron
regeneration in the gut barrier (Enamorado et al., 2023). In
vitro studies have shown that Th17-derived IL-17 and IL-22 can
penetrate the BBB and promote neuron death in (Kebir et al., 2007;
Wojkowska, Szpakowski & Glabinski, 2017). Despite this role, Th17
lymphocytes and γδ T cells have mostly been related with a detrimental
effect on cognitive function in ARDs (Komiyama et al., 2006; Lees,
Iwakura & Russell, 2008). Studies in aged individuals are needed to
assess the real impact of this cytokine on neuron viability and
regeneration in the context of inflammaging.
The Treg cell population has been shown to undergo changes with age,
with an increase in naturally occurring Treg cells (nTregs) and a
decline in inducible Treg (iTreg) in peripheral blood of both mice and
humans. This increase is reported in both CD4+ and
CD8+ Treg cells and correspond to a memory phenotype,
similar to the effector subsets (Jagger, Shimojima, Goronzy & Weyand,
2014). While these suppressive cells have been shown to slow the
progression of some ARDs (McGeachy, Stephens & Anderton, 2005;
Tennakoon, Mehta, Ortega, Bhoj, Racke & Karandikar, 2006), their
presence and activity in the aging brain, and their relationship with
cognitive function in the absence of disease, have yet to be fully
understood.
It is evident that T cells and inflammaging have a detrimental effect on
cognitive function. However, many questions remain unanswered, such as
the functional competence of Tregs or the composition of the cytokine
milieu within the parenchyma. Further research is needed to elucidate
and distinguish the different mechanisms playing a role, with the aim of
identifying potential therapeutic strategies to slow down aging and
decrease the risk to ARDs development.