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\begin{document}

\title{UPDATE ON THE ROLE OF T CELLS IN COGNITIVE IMPAIRMENT}



\author[1]{Ignacio Ruiz-Fernandez}%
\author[1]{Raquel Sanchez-Diaz}%
\author[1]{Enrique Ortega-Sollero}%
\author[1]{Pilar  Martín}%
\affil[1]{Centro Nacional de Investigaciones Cardiovasculares Carlos III}%


\vspace{-1em}



  
  \date{March 13, 2025}


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\selectlanguage{english}
\begin{abstract}
The central nervous system (CNS) has long been considered an
immune-privileged site, with minimal interaction between immune cells,
particularly of the adaptive immune system. Previously, the presence of
immune cells in this organ was primarily linked to events involving
disruption of the blood-brain barrier (BBB) or inflammation. However,
current research has shown that immune cells are found patrolling CNS
under homeostatic conditions. Specifically, T cells of the adaptive
immune system are able to cross the BBB and are associated with aging
and cognitive impairment. In addition, T-cell infiltration has been
observed in pathological conditions, where inflammation correlates with
poor prognosis. Despite ongoing research, the role of this population in
the aging brain under both physiological and pathological conditions is
not yet fully understood. In this review, we provide an overview of the
interactions between T cells and other immune and CNS parenchymal cells,
and examine the molecular mechanisms by which these interactions may
contribute to normal brain function and the scenarios in which
disruption of these connections lead to cognitive impairment. A
comprehensive understanding of the role of T cells in the aging brain
and the underlying molecular pathways under normal conditions could pave
the way for new research to better understand brain disorders.%
\end{abstract}%



\sloppy


\textbf{Update on the role of T cells in cognitive impairment}

\textbf{AUTHORS}

Ignacio Ruiz-Fern\selectlanguage{ngerman}ández\textsuperscript{1}, Raquel
Sánchez-Díaz\textsuperscript{1,2}, Enrique
Ortega-Sollero\textsuperscript{1}, Pilar Martín*\textsuperscript{1,2}

\emph{Short summary:} Exploring the Interactions Between T Cells and the
Central Nervous System: Implications for Brain Function and Disease

\emph{1 Centro Nacional de Investigaciones Cardiovasculares (CNIC),
Madrid, Spain; ignacio.ruiz@cnic.es (I.R.F); rsanchez@cnic.es (R.S.D);
joseenrique.ortega@cnic.es (E.O.S)}

\emph{2 CIBER de Enfermedades Cardiovasculares (CIBER-CV), Madrid,
Spain}

\emph{* Correspondence: Pilar Martín, PhD.} Centro Nacional de
Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain. Email:

\emph{pmartinf@cnic.es; Tel.: +34 91 453 1200 (ext 2009)}



\textbf{ABSTRACT}

The central nervous system (CNS) has long been considered an
immune-privileged site, with minimal interaction between immune cells,
particularly of the adaptive immune system. Previously, the presence of
immune cells in this organ was primarily linked to events involving
disruption of the blood-brain barrier (BBB) or inflammation. However,
current research has shown that immune cells are found patrolling CNS
under homeostatic conditions. Specifically, T cells of the adaptive
immune system are able to cross the BBB and are associated with aging
and cognitive impairment. In addition, T-cell infiltration has been
observed in pathological conditions, where inflammation correlates with
poor prognosis. Despite ongoing research, the role of this population in
the aging brain under both physiological and pathological conditions is
not yet fully understood. In this review, we provide an overview of the
interactions between T cells and other immune and CNS parenchymal cells,
and examine the molecular mechanisms by which these interactions may
contribute to normal brain function and the scenarios in which
disruption of these connections lead to cognitive impairment. A
comprehensive understanding of the role of T cells in the aging brain
and the underlying molecular pathways under normal conditions could pave
the way for new research to better understand brain disorders.

\textbf{ABBREVIATIONS}

AD: Alzheimer's disease

AIS: acute ischemic stroke

APC: Antigen-presenting cell

ARD: Age-related disease

A\selectlanguage{greek}β: β-\selectlanguage{english}amyloid

BBB: Blood-brain barrier

BCPB: Blood-chroroid plexus barrier

CNS: Central nervous system

CP: Choroid plexus

CSF: Cerebrospinal fluid

EAE: experimental autoimmune encephalomyelitis

IFN\selectlanguage{greek}γ; \selectlanguage{english}Interferon gamma

IL: Interleukin

MS: Multiple sclerosis

PD: Parkinson's disease

SAS: Subarachinoid space

SASP: Senescence-associated secretory phenotype

Th1: T helper 1

Th17: T helper 17

Th2: T helper 2

TNF\selectlanguage{greek}α: \selectlanguage{english}Tumor necrosis factor alpha

Treg: T regulatory cells

\textbf{1. INTRODUCTION}

For decades, the central nervous system (CNS) has been considered an
immune-isolated organ, due to the lack of lymphatic vessels and the
restriction of the blood-brain barrier (BBB), which limits the access of
immune cells (Arcuri, Mecca, Giambanco \& Donato, 2019; Mapunda, Tibar,
Regragui \& Engelhardt, 2022). However, recent studies have shown
evidence of the presence of immune cells in both physiological and
pathological conditions within the CNS (Arcuri, Mecca, Giambanco \&
Donato, 2019; Stephenson, Nutma, van der Valk \& Amor, 2018). The use of
lymphatic-cell-reporter mice has demonstrated the existence of classic
lymphatic vessels within the layers of the meninges and the presence of
adaptive immune cells, such as T and B lymphocytes, in these vessels
under homeostatic conditions (Buckley \& McGavern, 2022; Louveau et al.,
2015).

The meninges protect the brain and spinal cord and consist of three
different layers. The outermost layer, the dura mater, is a collagenous
membrane that is richly vascularized and innervated, and contains
numerous lymphatic vessels (Mapunda, Tibar, Regragui \& Engelhardt,
2022; Rua \& McGavern, 2018). The middle layer, the arachnoid mater,
primarily regulates molecules transport (Yasuda et al., 2013) and the
innermost layer, the pia mater, surrounds the parenchyma of the CNS.
Together, the arachnoid and pia maters are referred to as the
leptomeninges (Decimo, Fumagalli, Berton, Krampera \& Bifari, 2012).
Between these two lies the subarachnoid space (SAS), composed of
trabeculae and collagen fibers. The cerebrospinal fluid (CSF), produced
by the ependymal cells of the choroid plexus (CP), flows through this
space (Rua \& McGavern, 2018). The dural lymphatic vessels reabsorb the
CSF from the SAS through glymphatic system (Buckley \& McGavern, 2022;
Prinz \& Priller, 2017) (Figure 1).

Dysregulation of the CNS immune response can lead to the development of
autoimmune diseases, such as multiple sclerosis (MS) (Ransohoff, 2016).
A thorough comprehension of the role of T cells in this scenario, as
well as the molecular processes underlying age-related changes under
normal conditions, could provide new opportunities for research on
understanding the brain in autoimmune and neurodegenerative diseases.

\textbf{2. T LYMPHOCYTES IN THE HEALTHY BRAIN}

\textbf{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\textsuperscript{+} 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\textsuperscript{+} 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\textsuperscript{+} cells
comprise 48.95\%, CD8\textsuperscript{+} cells represent 17.61\%, double
positive CD4\textsuperscript{+}CD8\textsuperscript{+} cells represent
9.63\%, regulatory T cells (Treg) constitute 2.49\%, and natural killer
(NK) cells make up 3.45\%. The ratio of CD4\textsuperscript{+} T cells
to CD8\textsuperscript{+} T cells is estimated to be around 3.1 to 1.
(Piehl et al., 2022; Ransohoff \& Engelhardt, 2012). .

\textbf{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 \emph{Il4} \textsuperscript{-/-} mice (Derecki et al., 2010).
Additionally, T lymphocyte-secreted interferon gamma (IFN\selectlanguage{greek}γ\selectlanguage{english}) has also
been shown to participate in social behaviour. The restoration of normal
social behavior in \emph{Ifng} \textsuperscript{-/-} mice was achieved
through repopulation with wild-type T cells. IFN\selectlanguage{greek}γ \selectlanguage{english}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\textsuperscript{+} 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
as\emph{Htr7} (Iellem, 2001; Ito et al., 2019). The main functions of
Treg cells in the CNS are to control IFN\selectlanguage{greek}γ \selectlanguage{english}and tumor necrosis factor
alpha (TNF\selectlanguage{greek}α\selectlanguage{english}) secretion by immune cells through their inactivation, and
to moderate acute inflammation by secreting IL-10 (Liesz et al., 2009).
\selectlanguage{greek}γδ \selectlanguage{english}T lymphocytes can be seen in the meninges, CSF and brain parenchyma
after brain injury. Two different subsets have been identified, either
producing IFN\selectlanguage{greek}γ \selectlanguage{english}or IL-17. After neuronal development, fetal \selectlanguage{greek}γδ \selectlanguage{english}T cells
persist in the meningeal spaces throughout life. These T cells mainly
belong to the IL-17-producer subset. IL-17-secreting \selectlanguage{greek}γδ \selectlanguage{english}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 \selectlanguage{greek}γ\selectlanguage{english}t (ROR\selectlanguage{greek}γ\selectlanguage{english}t) 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 IFN\selectlanguage{greek}γ \selectlanguage{english}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 \selectlanguage{greek}γδ \selectlanguage{english}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 \emph{C.elegans}(Norris
\& Kipnis, 2019).

In addition to cytokines, CD4\textsuperscript{+} 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\textsuperscript{+} T cell subset is able to sense norepinephrine,
which is secreted by white adipose tissue-resident macrophages (Norris
\& Kipnis, 2019).

\textbf{3. INFLAMMAGING AND COGNITIVE IMPAIRMENT}

\textbf{3.1. Aging and age-related diseases}

Throughout the lifespan of an organism, all cell types experience
gradual changes that affect their performance either directly or
indirectly. This process, known as aging, is a compendium of different
cellular and molecular processes, such as DNA-related changes,
mitochondrial dysfunction or epigenetic alterations (Lopez-Otin, Blasco,
Partridge, Serrano \& Kroemer, 2013) that result in morbidity and
increased risk of chronic diseases referred to as age-related diseases
(ARDs) (Franceschi et al., 2018). Among these, conditions that affect
the CNS are frequent, including Alzheimer's disease (AD) or Parkinson's
disease (PD).

The complex aging phenomenon is one of the most challenging questions
for humanity to comprehend. It is important to differentiate between
age-associated pathologies and the normal, steady aging process, if such
distinction exists. This is a complex paradigm where the boundaries are
difficult to stablish. One of the running hypotheses is the continuum
hypothesis, which suggests that the aging process and age-related
diseases exist on a spectrum, with some individuals experiencing
accelerated aging and developing one or more ARDs and others
experiencing slower aging and remaining healthy (Franceschi et al.,
2018). Studies have found that even seemingly healthy individuals often
shows signs of pathology upon \emph{post-mortem} examination, such as
Lewy bodies, \selectlanguage{greek}β-\selectlanguage{english}amyloid (A\selectlanguage{greek}β\selectlanguage{english}) plaques or microvascular brain injuries of
their brains (Sonnen et al., 2011), leading to increased interest in
understanding the molecular hallmarks of aging, prevent and treat ARDs
(Franceschi et al., 2018).

However, some experts consider the aging process is just one of the
susceptibility factors that contribute to ARD development. Other aspects
such as genetic predisposition of age-unrelated genes or exposure to
exogenous agents play important roles and the balance of those determine
the outcome (Nelson et al., 2011). In this case, a ``healthy way of
aging'' would potentially exist with no collateral ARDs but still
different to the phenotype of young individuals. Until this topic is
fully explored, this review considers homeostatic aging to be the
absence of clinically noticeable pathologies.

\textbf{3. 2. Inflammaging and immunosenescence}

Recently, chronic inflammation has been identified as one of the
hallmarks of aging (Schmauck-Medina et al., 2022) and a strong
connection to most ARDs, including those involving cognitive decline.
The term ``inflammaging'' has been coined to describe the low-grade
systemic inflammation caused by modifications in the immune cells over
time, known as immunosenescence. All immune cell subsets are affected,
but T cells experience a significant impact. One notable change is a
reduced responsiveness to new antigens, which is caused by the reduction
in the na\selectlanguage{ngerman}ïve T cell pool. This reduction is caused by the combination of
thymic involution and the increase in the memory compartment due to
continuous exposure to a myriad of antigens since birth (Aiello et al.,
2019; Mittelbrunn \& Kroemer, 2021). The accumulation of terminally
differentiated T cells leads to the loss of co-stimulatory molecules
CD28 and CD27, which occurs upon clonal expansion, and upregulation of
CD57 and killer cell lectin-like receptor subfamily G member 1 (KLRG1)
cytotoxic markers (Aiello et al., 2019; Rodriguez et al., 2020).
Altogether, this senescent T cell pool is antigen-independent and highly
differentiated, which is the perfect trigger to the release of the
pro-inflammatory cytokines (IFN\selectlanguage{greek}γ, \selectlanguage{english}TNF-\selectlanguage{greek}α, \selectlanguage{english}IL-2 and IL-6) that
characterizes the inflammaging status (Mittelbrunn \& Kroemer, 2021;
Rodriguez et al., 2020). Moreover, the senescence-associated secretory
phenotype (SASP) adopted by immune and non-immune cells in older
organisms further promotes inflammation through the release of cytokines
and chemokines such as IL-6, IL-8 or IL-1\selectlanguage{greek}β, \selectlanguage{english}which boost the action of
innate cells, and Th1 and Th17 populations (Rea, Gibson, McGilligan,
McNerlan, Alexander \& Ross, 2018). Morover, exhausted T cells become
poor cytokine producers, an extensive profiling study revealed the
existence of a distinct age-related CD8\textsuperscript{+} T cell
secreting high levels of granzyme K. Such environment exacerbates the
SASP from senescent cells, perpetuating the inflammaging status
(Mogilenko et al., 2021).

\textbf{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-1\selectlanguage{greek}β \selectlanguage{english}and TNF\selectlanguage{greek}α,
\selectlanguage{english}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\textsuperscript{+} 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 IFN\selectlanguage{greek}γ-\selectlanguage{english}expressing
CD8\textsuperscript{+} 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). \emph{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 \selectlanguage{greek}γδ \selectlanguage{english}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\textsuperscript{+} and
CD8\textsuperscript{+} 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.

\textbf{4. BRAIN T CELLS IN NEURODEGENERATIVE DISEASES}

\textbf{4.1. T cells in Alzheimer's disease}

AD is the most prevalent neurodegenerative disorder among elderly
adults, often progressing to dementia. It primarily manifests as
cognitive impairments, including memory loss, language difficulties,
misidentifications, and behavioral disturbances. These symptoms are
linked to two protein changes in the brain. The first is
hyperphosphorylation of the Tau protein, resulting in the formation of
intracellular neurofibrillary tangles. The second is the formation of
extracellular A\selectlanguage{greek}β-\selectlanguage{english}peptide deposits, leading to the creation of amyloid
plaques. Both of these processes result in synaptic loss and damage to
neurons, contributing to the decline in cognitive function.

T cells, as fundamental cells in the adaptive immune system, may have
different roles in the progression of the disease and either may
contribute to the aggravation of the pathology or have a protective
function in other cases (Table 2). Aberrant T cells may indirectly
influence the pathogenesis of AD by secreting proinflammatory cytokines
that maintain a detrimental neuroinflammatory state. However, the
multifactorial role of T cells in the pathogenesis of AD is also related
to an immune response to disease risk factors: the apolipoprotein E
(APOE), A\selectlanguage{greek}β \selectlanguage{english}peptide, secretases or Tau protein.

The \emph{APOE} gene plays a significant role in AD by influencing the
Tau neurotoxicity (Kang et al., 2021), and regulating the levels of Th17
and Treg cells. The specific allele of the APOE protein is crucial, as
individuals with the APOE4 allele have higher levels of T cell
activation and a higher risk of developing AD (Bonacina et al., 2018).
As a result, this gene may be considered a potential target for
controlling abnormal T cell activation in AD (Dai \& Shen, 2021).

The presence of A\selectlanguage{greek}β-\selectlanguage{english}reactive T cells is a result of APCs presenting
either the A\selectlanguage{greek}β \selectlanguage{english}precursor protein (APP) or A\selectlanguage{greek}β \selectlanguage{english}peptide, cleaved by \selectlanguage{greek}β- \selectlanguage{english}and
\selectlanguage{greek}γ-\selectlanguage{english}secretases. Both APP and exogenous A\selectlanguage{greek}β \selectlanguage{english}can directly modulate T cell
function. Additionally, expression of the precursor by monocytes
triggers the release of proinflammatory cytokines, which indirectly
activate T cells (Dai \& Shen, 2021). The role of A\selectlanguage{greek}β-\selectlanguage{english}reactive T cells
remains controversial, as some animal studies have shown them to be
beneficial in clearing A\selectlanguage{greek}β \selectlanguage{english}peptides through IFN\selectlanguage{greek}γ-\selectlanguage{english}mediated activation of
microglia (Fisher, Nemirovsky, Baron \& Monsonego, 2010), while others
suggest that these T cells can strongly activate proinflammatory
cytokines such as IL-6, TNF\selectlanguage{greek}α \selectlanguage{english}and IL-1\selectlanguage{greek}β, \selectlanguage{english}contributing to a
neuroinflammatory and neurotoxic environment (Mietelska-Porowska \&
Wojda, 2017).

T cells have the ability to control the enzymes responsible for APP
processing. T cell-mediated biological changes regulate the expression
and activity of \selectlanguage{greek}β-\selectlanguage{english}secretase, and in turn, influence T cell function.
Furthermore, the Notch family of receptors are substrates of
\selectlanguage{greek}γ-\selectlanguage{english}secretase, which releases the Notch intracellular domain (NICD) during
proteolysis for translocation to the nucleus and activation of
transcription factors involved in T cell development (Dai \& Shen,
2021). Additionally, \selectlanguage{greek}α-\selectlanguage{english}secretase, which promote a non-amyloidogenic
cleavage of APP, is also involved in T cell function by processing
various substrates, while T cells promote \selectlanguage{greek}α-\selectlanguage{english}secretase activation.

The presence of T cells in the brain is correlated with Tau pathology
and can result in excessive T cell activation (Merlini, Kirabali, Kulic,
Nitsch \& Ferretti, 2018). In summary, T cells in AD may have a dual
role. On the one hand, they can migrate into the CNS parenchyma and
contribute to neuronal death during AD progression. However, T cell
infiltration in the CNS parenchyma may also have a beneficial effect by
promoting the restoration of glial function. In normal conditions, the T
cell infiltrate in the CNS parenchyma has a neuroprotective role in
spatial learning and preserving neurogenesis (Dai \& Shen, 2021). Thus,
it is important to thoroughly understand the immune response in AD in
order to develop effective therapeutic strategies.

\textbf{4.2. T cells and Parkinson's disease}

PD is the second most prevalent neurodegenerative disorder that affects
the motor system and causes symptoms like tremors, stiffness,
bradykinesia, gait impairment and many non-motor symptoms. The symptoms
are linked to \selectlanguage{greek}α-\selectlanguage{english}synuclein inclusions and the loss of dopaminergic
neurons. Inflammation in the brain, specifically the role of
T-lymphocytes, can trigger a type 1 pro-inflammatory response, which may
initially have a protective effect, but eventually, the inflammation
becomes harmful and suppresses the type 2 anti-inflammatory response,
leading to a dysregulated state of neuroinflammation and consequent
dopaminergic neurodegeneration. Regulating the immune response is a
promising approach for managing the disease's pathogenicity and
improving the response to treatments (Baird, Bourdette, Meshul \& Quinn,
2019).

In both AD and PD, it is important to identify an early immune response
in peripheral blood, as this can be used as a diagnostic and prognostic
tool, and even as a means to regulate the progression of both diseases
through the use of immunomodulators., Increased levels of activated
lymphocytes, apoptosis susceptible lymphocytes, central memory T cells,
regulatory T and B cells have been found in both diseases.
Characteristic immune cells in AD and PD include
CD4\textsuperscript{+}CD38\textsuperscript{+} and
CD8\textsuperscript{+}CD38\textsuperscript{+} T lymphocytes, and
CD4\textsuperscript{+}CD69\textsuperscript{+} and
CD8\textsuperscript{+}CD69\textsuperscript{+} T cells in PD. Regulatory
T cells, such as CD19\textsuperscript{+} CD5\textsuperscript{+}
IL10\textsuperscript{+}in PD and AD, and CD19\textsuperscript{+}
CD5\textsuperscript{+}IL10\textsuperscript{+} FoxP3\textsuperscript{+},
CD4\textsuperscript{+}FoxP3\textsuperscript{+}
CD25\textsuperscript{+}CD45RO\textsuperscript{+} in PD, are also found
to play a role in both diseases. In AD, an increase of effector
CD4\textsuperscript{+}lymphocytes have been found in the early stages of
the disease, while a decrease of CD4\textsuperscript{+}
CD38\textsuperscript{+}CD38\textsuperscript{+} lymphocytes occur as the
disease progresses (Garfias et al., 2019).

\textbf{4.3. Autoimmunity in the brain: Multiple sclerosis}

It is known that deregulation of the immune system plays a crucial role
in neurological disorders. This is particularly evident in diseases
where the underlying pathology is autoimmune-related. MS is a chronic
autoimmune disease in which self-reactive T cell clones attack the
myelin component of the CNS. In early MS, active lesions are
characterized by focal demyelination of white matter accompanied by
perivenular infiltrates of immune cells such as CD8\textsuperscript{+} T
cells, CD20\textsuperscript{+} B cells, plasmablasts, and macrophages
that form a typical perivascular cuff. This demyelination disrupts the
BBB and causes progressive loss of neurological function due to damage
to the myelin sheath around the neuronal axons (Frischer et al., 2009).

Genetic predisposition to MS is linked to specific HLA class II
haplotypes (HLA-DR15 and HLA-DQ6), which are thought to present
autoantigens to the adaptive immune system. Other immune-related genes
have also been implicated in the development of MS, such as those
encoding for IL-17 and IL-2. In addition to genetics, various
environmental factors, such as lifestyle, vitamin deficiencies, and
infections such as EBV, have been identified as risk factors for MS.
Studying the immune response in the experimental autoimmune
encephalomyelitis (EAE) model has provided insight into the role of T
cell phenotypes and their effector mechanisms in the pathology of MS
(Pilli, Zou, Tea, Dale \& Brilot, 2017).

\textbf{4.3.1. Effector CD4\textsuperscript{+} T cells in MS}

The onset of MS is caused by the activation of specific myelin-specific
T lymphocytes in the peripheral compartment, which gain access to the
CNS through the expression of appropriate adhesion molecules and
receptors in the BBB. Once inside the brain, T cells are reactivated by
self-antigens presented by resident APCs, leading to the manifestation
of the disease and demyelination of neurons. Research has shown that
autoreactive CD4\textsuperscript{+} T cells can recognize myelin sheath
proteins, such as myelin basic protein (MBP), myelin-associated
glycoprotein (MAG), and myelin oligodendrocyte glycoprotein (MOG), in
both MS patients and healthy individuals. However,
CD4\textsuperscript{+} T cells in MS patients exhibit an activated and
memory phenotype with a higher affinity for these proteins compared to
naive myelin-specific CD4+ T cells from healthy controls.

The former understanding of the primary effector cell in EAE and MS was
believed to be Th1, but recently Th17 lymphocytes were shown to induce
other cell types to produce proinflammatory mediators such as IL-6,
GM-CSF, matrix metalloproteases and CXC chemokines, including CXCL8 (a
powerful neutrophil chemoattractant), suggesting that Th17 cells may
contribute to inflammation in the CNS. This is supported by the fact
that the infusion of Th17 cells worsens EAE progression, while the
infusion of Th1 cells does not have a significant effect. Additionally,
an increase in IL-17 transcripts has been observed in chronic MS lesions
compared to acute lesions or healthy individuals, further supporting the
role of Th17 cells in autoimmunity in the brain (Komiyama et al., 2006).

\textbf{4.3.2. CD8} \textsuperscript{+} \textbf{T cells in MS}

The role of CD8\textsuperscript{+} T cells in CNS autoimmunity has
recently gained attention, despite the focus of research traditionally
being focused on CD4\textsuperscript{+} T cells. (Goverman, Perchellet
\& Huseby, 2005). Although depleting CD4\textsuperscript{+} T
lymphocytes in MS patients has not led to improvement, alemtuzumab,
which targets both CD4\textsuperscript{+} and CD8\textsuperscript{+} T
cells, has been found to have a positive impact. Further,
CD8\textsuperscript{+} lymphocytes have been found in MS lesions and CSF
of these patients (Friese \& Fugger, 2005). The activity of
CD8\textsuperscript{+} T cells in the pathology of CNS autoimmunity is
still not well understood, but some studies suggest that they can play
either a beneficial or harmful role. Depletion of
CD8\textsuperscript{+}T lymphocytes results in a lower mortality rate in
EAE models, suggesting a regulatory role coinciding with stages of
disease remission. However, specific myelin-reactive
CD8\textsuperscript{+} T cells have also been reported to be highly
pathogenic for the disease, and infusion of MBP-reactive
CD8\textsuperscript{+} T cells in healthy animals induces demyelination,
clearly demonstrating their role in pathogenesis (Huseby, Liggitt,
Brabb, Schnabel, Ohlen \& Goverman, 2001). Further research is needed to
fully understand the activity of CD8\textsuperscript{+} T cells in CNS
autoimmunity and their potential to regulate or contribute to pathology.

\selectlanguage{greek}\textbf{4.3.3. γδ T cells in MS}\selectlanguage{english}

Despite limited research, there are some studies that associate \selectlanguage{greek}γδ \selectlanguage{english}T
cells with the pathogenesis of MS and EAE. However, their exact role in
the process remains uncertain. \selectlanguage{greek}γδ \selectlanguage{english}T cells have been found to accumulate
in MS plaques, displaying oligoclonal expansion, which is an indication
of their involvement in antigen-specific responses (Blink \& Miller,
2009). Like CD8\textsuperscript{+} T lymphocytes, \selectlanguage{greek}γδ \selectlanguage{english}T cells appear to
have a dual role in the pathology. On the one hand, they may have a
regulatory effect in EAE, as studies that depleted \selectlanguage{greek}γδ \selectlanguage{english}T cells resulted
in a more severe disease and mice lacking \selectlanguage{greek}γδ \selectlanguage{english}T cells exhibited a reduced
ability to achieve remission from EAE. On the other hand, studies
suggest a pathogenic role for \selectlanguage{greek}γδ \selectlanguage{english}T cells in EAE, as they contribute to a
proinflammatory environment and are a primary source of IL-17 and other
proinflammatory cytokines in the disease (Komiyama et al., 2006; Lees,
Iwakura \& Russell, 2008; Ponomarev \& Dittel, 2005). Therefore, more
research is necessary to determine the circumstances under which \selectlanguage{greek}γδ \selectlanguage{english}T
cells may change their role, particularly if these cells are to be
explored as a therapeutic target.

\textbf{4.3.4. CD4} \textsuperscript{+} \textbf{Regulatory T cells in
MS}

In TCR transgenic mouse models specific for myelin,
CD4\textsuperscript{+} FOXP3\textsuperscript{+} Treg cells prevent
spontaneous EAE by suppressing CD4\textsuperscript{+}myelin-specific T
cell activation in the periphery. MBP-specific T cells acquire an
anti-inflammatory phenotype after encountering endogenous antigen
presented on lymphoid tissues in the presence of Treg cells (Cabbage,
Huseby, Sather, Brabb, Liggitt \& Goverman, 2007). However, if Treg
cells are absent or immunogenic stimuli are present during the
interaction between MBP-specific T cells and peripheral APCs, tolerance
is not generated and autoimmunity prevails. The function of Treg cells
in preventing inflammation within the CNS is also controversial
(McGeachy, Stephens \& Anderton, 2005) Although there is a correlation
between the presence of IL-10-producing FOXP3\textsuperscript{+} Treg
cells and recovery of the CNS and disease, Treg cells appear to be
ineffective in suppressing effector T cells in the CNS until local
levels of IL-6 and TNF\selectlanguage{greek}α \selectlanguage{english}decrease. Currently, the mechanisms of
suppression, antigen specificity and efficacy of Treg cells in
suppressing Th1, Th17 and CD8\textsuperscript{+} T cells in the CNS are
not elucidated. The function of CD4\textsuperscript{+} Treg cells in the
peripheral blood of MS patients appears to be compromised, indicating a
weakened ability to restrain the activation of T cells that target
myelin in the peripheral compartment. In MS tissue sections, the
presence of FOXP3\textsuperscript{+} Treg cells has not been detected.
However, it is unclear whether their absence is a result of a migration
defect or reduced survival in the CNS. (Tzartos et al., 2008).

\textbf{4.3.5. Regulatory CD8} \textsuperscript{+} \textbf{T cells in
MS}

The presence of regulatory CD8\textsuperscript{+} T cells have been
observed in both EAE and MS patients. Different subtypes of regulatory
CD8\textsuperscript{+} cells are involved in inhibiting effector
CD8\textsuperscript{+} T cells, including natural
CD8\textsuperscript{+}CD122\textsuperscript{+} T cells, which secrete
IL-10 to inhibit effector CD8\textsuperscript{+} T cells;
HLA-G\textsuperscript{+} CD8\textsuperscript{+} T cells, which suppress
effector T cells through the secretion of soluble factors; induced
CD8\textsuperscript{+} Tregs that act at the CNS level; and
CD8\textsuperscript{+}CD28\textsuperscript{-} T cells that can induce
tolerogenic effects on dendritic cells and inhibit disease.
CD8\textsuperscript{+} Tregs generated by the expansion of
CD4\textsuperscript{+} effector T cells in the periphery can eliminate
activated CD4\textsuperscript{+} T cells by recognizing the
non-classical MHC molecule Qa-1 on their surface. Modulating
CD8\textsuperscript{+} and CD4\textsuperscript{+} Treg responses may
have therapeutic potential for MS patients. MS patients vaccinated with
myelin-specific CD4\textsuperscript{+} T cell clones generate
CD8\textsuperscript{+} Tregs capable of eliminating effector T cells.
The benefits of glatiramer acetate therapy, commonly administrated to MS
patients, may also be mediated partly by the regulation of
CD8\textsuperscript{+} T cells (Tennakoon, Mehta, Ortega, Bhoj, Racke \&
Karandikar, 2006).

\textbf{4.4. Ischemic stroke}

Under physiological conditions, brain barriers maintain homeostasis of
the CNS by protecting the parenchyma from the constantly changing
bloodstream (Mapunda, Tibar, Regragui \& Engelhardt, 2022). As discussed
previously, these barriers divide the CNS into different compartments
that have varying levels of permeability to innate and adaptive immune
cells. Another condition that alters the BBB is the ischemic stroke.
During this event, an imbalance between proinflammatory and
anti-inflammatory immune populations contributes to BBB disruption
through several mechanisms. Activated proinflammatory T cells directly
damage the BBB by producing cytokines. The secretion of IFN\selectlanguage{greek}γ, \selectlanguage{english}IL-17 and
IL-21 by Th1 and Th17 cells in the acute phase of ischemic stroke
degrades tight junctions (TJ), leading to increased permeability and
reduced integrity of the BBB. \selectlanguage{greek}γδ \selectlanguage{english}T cells play a pathogenic role by
producing IL-17, which decreases the expression of occludin and zonula
occludens-1 (ZO-1), increasing BBB permeability. Monocytes and
neutrophils are also recruited due to increased expression of CCL2 and
CXCL1 in endothelial cells. (Wojkowska, Szpakowski \& Glabinski, 2017).
IL-17 also degrades endothelial TJ by boosting ROS generation through
NADPH oxidase or xanthine oxidase (Huppert et al., 2010). However, Th17
cells produce IL-26, a BBB-protective cytokine by upregulating the
expression of occludin, claudins and ZO-1 in endothelial cells. During
oxygen-glucose deprivation, NK cells can increase the permeability of
the brain microvascular endothelium through the production of IFN\selectlanguage{greek}γ \selectlanguage{english}and
reactive oxygen species. CD8\textsuperscript{+} T cells can also
contribute to BBB permeability by inducing cytotoxicity, secreting
granzyme B, FasL, TNF\selectlanguage{greek}α, \selectlanguage{english}and IFN\selectlanguage{greek}γ, \selectlanguage{english}and degrading claudin-5. After an
ischemic event, Treg cells, which regulate the immune response, are
decreased. However, Tregs and Th2 cells play a protective role in the
ischemic hemisphere by preventing an excessive immune response that
could cause secondary injury (Stubbe et al., 2013). The presence of
Tregs after an acute ischemic stroke (AIS) controls the overactivity of
resident microglia and infiltrated T cells. Through the upregulation of
IL-10 and TGF\selectlanguage{greek}β, \selectlanguage{english}Tregs reduce the levels of proinflammatory factors such
as TNF\selectlanguage{greek}α, \selectlanguage{english}IFN\selectlanguage{greek}γ \selectlanguage{english}and IL-1\selectlanguage{greek}β. \selectlanguage{english}Furthermore, Tregs restrict the production of
matrix metallopeptidase 9 in neutrophils through crosstalk of programmed
death 1 (PD-1) and its ligand (PD-L1), leading to improved BBB integrity
(Qiu et al., 2021).

The sequence of immune cell appearance and duration of persistence in
the aftermath of the AIS has been characterized. Neutrophils are the
first to swarm the tissue and reach their highest level of infiltration
at 24 hours, followed by a peak in monocyte presence at 3-7 days. T
cells begin to extravasate at 24 hours and reach their peak at 3 days,
but remain persistent over time and can still be detected even one month
after the stroke (Gill, Sivakumaran, Aravind, Tank, Dosh \& Veltkamp,
2018). Double negative T cells (DNT) and CD8\textsuperscript{+} T
lymphocytes can be observed within the first 24 hours with their peak at
3 days (Liesz et al., 2009), while CD4\textsuperscript{+} T cells are
found at 24 hours and Tregs appear later but are more persistent over
time (Chu et al., 2014; Stubbe et al., 2013). The recruitment of Treg
and \selectlanguage{greek}γδ \selectlanguage{english}T cells is governed by the CCL5/CCR5 and CCL6/CCR6 axis,
respectively, while NK cells are dependent on the IP10/CXCR3 and
CX3CL1/CX3CR1 axis, with the latter having a shorter duration over time
(Gan et al., 2014). Clinical research has revealed that differentiation
of T lymphocyte groups towards proinflammatory subpopulations occurs
after stroke.

Following an AIS, the number of Treg cells decreases dramatically,
leading to a weak immune response. This is due to a decrease in the
number of CD39+ Treg cells, which results in a decline in the production
of anti-inflammatory cytokines such as TGF\selectlanguage{greek}β \selectlanguage{english}and IL-10 (Ruhnau et al.,
2016). Conversely, there is a rise in proinflammatory populations,
including Th17 lymphocytes and \selectlanguage{greek}γδ \selectlanguage{english}T cells. An increase in
CD4\textsuperscript{+} CD28\textsuperscript{+} T cells has also been
linked to increased tissue damage in the aftermath of an AIS (Dolati et
al., 2018). Additionally, the number of T-cell immunoglobulin and
mucin-domain containing-3 (TIM-3), mediated by a Th1 response,
increases, along with TNF\selectlanguage{greek}α, \selectlanguage{english}leading to a heightened inflammatory
response (Dolati et al., 2018; Huppert et al., 2010; Zhao et al., 2011).

It is important to note that these immune responses are connected to the
digestive system through the gut-brain axis. After an ischemic stroke,
the gut microbiome can become imbalanced, leading to either
amplification or reduction of the immune response. Therefore,
controlling the gut microbiome may be a potential strategy for
mitigating the impact of ischemic strokes (Li et al., 2019).

\textbf{5. T CELLS AS THERAPEUTIC TARGET}

The modulation of T cell-mediated immune response is of particular
interest in diseases such as MS, where successful first-line
immunotherapies and monoclonal antibody therapies, such as Natalizumab,
are used to treat patients with severe symptoms (Warnke et al., 2010).
Natalizumab targets the \selectlanguage{greek}α\selectlanguage{english}4\selectlanguage{greek}β\selectlanguage{english}1 integrin on T cells, preventing them from
binding to VCAM1 on BBB endothelial cells and entering the CNS. This is
demonstrated by the marked decrease in various T cell populations in the
CSF of MS patients treated with natalizumab compared to controls (Stuve
et al., 2006). However, treatment with this antibody in these patients
can result in various immune deficiencies, such as opportunistic
infections and leukoencephalopathies (Warnke, Olsson \& Hartung, 2015).

The sphingosine 1-phosphate receptors (S1PRs) S1PR1, S1PR3, S1PR4, and
S1PR5 are expressed in many cell types, including lymphocytes and
endothelial cells. They play a crucial role in regulating biological
processes, such as lymphocyte trafficking and vascular permeability. The
use of S1PR modulators, such as Fingolimod, Siponimod, Ozanimod, or
Ponesimod, which are approved for the treatment of MS, helps to reduce
the trafficking of immune cells to the CNS (Mapunda, Tibar, Regragui \&
Engelhardt, 2022). However, due to the multifactorial nature of this
autoimmune disease, it is important to continue searching for new
autoantigens to provide more targeted and effective treatments with
minimal side effects.

The regulation of the immune response can also be of interest in
diseases other than those with a clear immunological component. In the
case of AIS, preclinical approaches aim to alleviate its adverse
effects, such as using monoclonal antibodies like anti-VLA4, which
blocks CD49d (Liesz et al., 2011) or FTY720/Fingolimod, an agonist of
S1P1 receptors (Salas-Perdomo et al., 2019). These aim to prevent immune
cells from infiltrating the CNS. Regulators of immune homeostasis, such
as Vitamin D and Resveratrol, which regulate PPAR\selectlanguage{greek}γ \selectlanguage{english}function (Matsuura,
Egi, Yuki, Horikawa, Satoh \& Akira, 2011), as well as modulators of the
intestinal microbiota (Dou, Rong, Zhao, Zhang \& Lv, 2019), like sodium
butyrate and valproic acid, have been shown to reduce infarct size and a
decrease in cognitive impairment.

The regulation of T cell-mediated responses in AD is not well explored
compared to other pathologies. While some preliminary studies have
investigated the use of monoclonal antibodies against A\selectlanguage{greek}β \selectlanguage{english}peptides and
phosphorylated Tau protein (Wisniewski \& Goni, 2015), and early-stage
clinical trials aimed at restoring the suppressive activity of Treg
cells by expanding them ex vivo (Faridar et al., 2020), a deeper
understanding is needed to effectively implement these therapies. The
APOE protein is an important modulator of T cell response and a powerful
risk factor in AD, making it an interesting target for regulating
abnormal T cell activation in this pathology.

The contribution of T cells to the development of PD has been well
established, leading to the development of numerous neuroprotective
therapies that show a T cell-mediated mechanism (Table 2). Specifically,
increasing the number or function of Tregs has been shown to be
effective in providing neuroprotection in the
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) induced mouse model
of PD. The recognition of the immune response's role in PD opens up new
opportunities for diagnosis and treatment. Identifying individuals with
HLA alleles that increase their risk for specific \selectlanguage{greek}α-\selectlanguage{english}synuclein-specific T
cells could lead to early diagnosis and treatment. Additionally, these
clonal T cells could be used as early biomarkers of disease, identifying
self-protein autoimmunity before motor symptoms develop. One promising
avenue of treatment is Sargramostim, a granulocyte-macrophage
colony-stimulating factor, which has been used to treat patients
receiving bone marrow transplants or undergoing cancer treatment, by
promoting myeloid recovery and inducing Treg responses. Results from a
phase I clinical trial show that patients receiving the drug showed
improvement after 6-8 weeks of treatment, with increased numbers and
function of Tregs compared to patients receiving a placebo. Additional
clinical research will shed light on the potential of immunomodulatory
drugs for the treatment of PD (Garretti, Agalliu, Lindestam Arlehamn,
Sette \& Sulzer, 2019).

\textbf{6. CONCLUSION}

T cells ability to mediate the immune response makes them a valuable
tool in treating conditions where the immune system plays a crucial
role. With advances in medical research and technology, techniques have
been developed to modulate T cell activity, offering new therapeutic
strategies for many medical conditions. The traditional belief that the
CNS is immune-isolated has been challenged by recent evidence of the
presence of immune cells within the CNS in both normal and pathological
conditions. T cells are demonstrated to enter the CNS through the
lymphatic vasculature and the fenestrated capillaries within the CP and
populate the dura mater and the CSF. Further understanding of T cells in
the CNS and the molecular processes behind these changes in normal
conditions can open up new avenues of research in autoimmune diseases
like MS, caused by T cells targeting myelin. The presence of T cells
also may play a role in AD and PD, with APOE as a key factor in AD and T
cell modulation as a potential treatment strategy in PD. The BBB
regulates the traffic of immune cells into the CNS, but pathological
conditions like MS and stroke can disrupt it. There are various
therapies that target T cells to reduce symptoms of MS such as
Natalizumab, Fingolimod, and others, while regulation of T cell-mediated
response is being explored in AD and Tregs in PD. T cells may also serve
as early biomarkers in PD.

However, T cells are not just crucial in pathological conditions, they
also play a fundamental role in aging. The aging process leads to a
decline in cellular and molecular function, resulting in chronic
diseases and increased risk of ARDs. Chronic inflammation, also known as
''inflammaging'', is a hallmark of aging linked to cognitive decline and
pathology. T cells are affected by aging and the accumulation of
senescent T cells leads to pro-inflammatory cytokine release. This
age-related systemic inflammation is connected to impaired cognitive
function. Despite this field is an active field of research, more
information is needed to fully understand the impact of T cell aging on
cognitive decline.

\textbf{ACKNOWLEDGMENTS}

This study was supported by competitive grants from the \selectlanguage{ngerman}\emph{Ministerio
de Ciencia e Innovación} (MCIN), through the Carlos III Institute of
Health (ISCIII)-\emph{Fondo de Investigación Sanitaria} (PI22/01759)
and\emph{Comunidad de Madrid} grant P2022/BMD-7209-INTEGRAMUNE-CM to
P.M. I.R-F. is supported by \emph{Formación de Profesorado
Universitario}(FPU20/05176) program from the Spanish Ministry of
Universities. The CNIC is supported by the Instituto de Salud Carlos III
(ISCIII), the Ministerio de Ciencia e Innovación (MCIN) and the Pro CNIC
Foundation, and is a Severo Ochoa Center of Excellence (grant
CEX2020-001041-S funded by MICIN/AEI/10.13039/501100011033).

\textbf{AUTHOR CONTRIBUTIONS}

I. R-F., R. S-D, E. O-S. and P.M.: writing original draft, collected
bibliography, designed figure and tables, and editing. I. R-F. and P.M.:
conceived the review and revised the manuscript.

\textbf{CONFLICT OF INTEREST}

R. S-D and P.M. are inventors on a patent (WO 2017/093353). All others
authors have no conflict of interest.

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\textbf{FIGURE LEGENDS}

\textbf{Figure 1. Schematic view of the role and location of T cell
subsets in homeostasis and inflammaging in the different compartments of
the brain.} In homeostatic conditions (left), the vascular BBB, the
blood-CSF barrier and the meningeal barrier limits the access of the T
cell population to the CNS. In the context of aging (right), these
barriers are compromised by the increased pro-inflammatory cytokine
release, allowing the entry of mostly CD8+ T cells, T regulatory cells
and other effector T cells into the parenchyma. If the contribution of
the different cytokine signatures results in a pro-inflammatory
microenvironment, the consequences on the resident immune cells, glia
and neurons would induce cognitive impairment.\selectlanguage{english}
\begin{figure}[H]
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