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.