CLA expression on human T cells and skin
The cutaneous lymphocyte-associated antigen (CLA) is a cell surface
molecule preferentially expressed on human memory T cells infiltrating
skin, in inflamed and non-inflamed situations, that it is not expressed
on T cells infiltrating extra-cutaneous sites.1 CLA is
a carbohydrate, a modified form of sialyl Lewis X
antigen,2 and is an epitope of the surface protein
P-selectin glycoprotein ligand-1 (PSGL-1).3 It can be
found on different human T-cell populations such as
CD45RO+ memory CD4+ and
CD8+ T cells, effector/central T
cells4 and it is expressed on about 15% of peripheral
blood T cells of healthy individuals.1 Other T-cell
subsets such as type 2 innate lymphoid cells (ILC)2,5ILC3,6 Vγ9Vδ2 T cells,7 and
NKG2D+ CD8+ T
cells8 express CLA. In addition, CLA is also expressed
by regulatory T cells (Treg)9 and
effector memory B cells.10 In human
CDR45RO+ T cells CLA is upregulated during the naïve
to memory transition by fucosyltransferase VII.11
CLA has been shown to be induced by the effect of IL-12 on freshly
generated Th1/Tc1 and Th2/Tc2 cells,12 ex vivoin human Th2 cells,13 as well as, by staphylococcal
enterotoxin B (SEB).14 At present, the functional
implications in AD of that other T-cell types expressing CLA, besides
the CD45RO+ subset, have not been clarified.
CLA+ T cells in skin migration and
skin-blood recirculation
Most T cells that home to skin are of the CD45RO+phenotype and express CLA.1 CLA functions as an
adhesion molecule when is recognized by the lectin domain of the
E-selectin present on endothelial cells,15,16 and
together with other adhesion interactions (LFA-1/ICAM-1, and
VLA-4/VCAM-1) and chemokines mediate transendothelial migration of
CLA+ T cells through the superficial vascular
plexus.17,18 The keratinocyte-derived chemokine
CCL27/CTACK (T cell-attracting chemokine) binds to CCR10, that is
preferentially expressed on CLA+ T
cells.19,20 CCL17/TARC (thymus and
activation-regulated chemokine), one of the best biomarkers of
AD,21 binds to CCR4, which is preferentially expressed
by CD4+ CLA+ memory T
cells.22 Moreover, CLA+ memory Th2
cells from AD lesional skin selectively migrate to human skin grafts
transplanted onto SCID mice in response to CCR4.23
Efalizumab, a LFA-1 targeting monoclonal antibody that blocks the
LFA-1/ICAM-1 interaction, led to AD clinical
improvement24 and reduction of cutaneous
CLA+ memory T cells.25 However,
during treatment, patients presented with secondary
CLA+ lymphocytosis, that recirculated into the skin
once treatment was interrupted, leading to disease exacerbation. There
is normal T-cell recirculation/turnover between peripheral tissues
(e.g. , skin) and blood. In that context, inflammatory cells can
migrate back from the skin to the blood.26 Thus, the
relevance of circulating CLA+ T cells in dermatology
not only relies on their capacity to selectively migrate to skin, but
also on their de-homing ability, implying that these circulating memory
T cells might reflect cutaneous immune responses.27Consistently, it has been shown that CLA+memory/effector T cells can be found in draining lymphatics of the
skin.28–30 This feature, added to the positive
correlation between the phenotype and amount of circulating
CLA+ T cells and AD severity, and the abundant
infiltrates of CLA+ T cells in AD lesional skin
(compared to controls),31 suggests that circulating
CLA+ T cells may serve as cellular peripheral
biomarkers in AD.32
CLA+ T cells also represent activated immune cells
that can migrate to various tissues and induce an inflammatory response.
Similar type of cellular migration has been demonstrated in the
circulation of patients with various chronic inflammatory
diseases.33–35 The frequency of allergen-specific T
cells have been reported in a frequency of one in
104-105 T cells. However, a type 2
immune response in allergies and asthma is not solely confined to
allergen-specific T cells. It harbors a wider skew in immune response
including skin-homing CLA+ type 2 T cells, chemokine
receptor Th2 (CRTH2)-expressing type T cells, ILC2, B cells and
CRTH2+ eosinophils.33,36,37 The
migration of activated T cells to other target organs of inflammation
has been demonstrated in food allergen-specific and skin-homing T cells
that are sensitized in the gut and can migrate into the skin causing
AD.35 Circulating T cells are highly active in
polyallergic patients and express chemokine receptors for the migration
to many different tissues.38 Such a mechanism could be
responsible for the atopic march of allergic diseases in the sequential
order of AD, food allergy, asthma, and allergic
rhinitis.39,40
These findings are in line with the epithelial barrier theory that
proposes that environmental exposure to certain substances, such as
detergents, surfactants, toothpastes, food emulsifiers and additives,
cigarette smoke, particulate matter, diesel exhaust, ozone,
nanoparticles and microplastics, might be toxic to our
cells.41–43 CLA+ T cells have been
proposed to be activated in the gut and migrate to skin. Disturbed gut
barriers by environmental substances may lead to local T cells
activation, that gain a skin-homing capacity and migrate to AD skin. The
barrier theory describes that pathogen colonization, particularlyStaphylococcus aureus (S. aureus) , altered microbiota
diversity, local inflammation, and incorrect regeneration and
remodelling, take place in tissues with a compromised epithelial
barrier. A myriad of chronic inflammatory diseases develop and worsen as
a consequence of inflammatory cells migration to remote tissues, which
also contributes to tissue damage and inflammation in distant
organs.44
CLA+ T cells in the human cutaneous immune
response
The skin-associated lymphoid tissue (SALT) was proposed by J. W.
Streilein 40 years ago based on several pieces of evidence, among
others, the existence of T cells with skin affinity and the ability to
recognize skin-associated antigens.45 Based on the
skin tropism, recirculation, and specific responses of
CLA+ T cells, it may be considered that this
population, constitutes the subset of CD45RO+population that is closer to SALT features and may be contemplated
representative of the skin-associated adaptive immune system (Table
I).46 Since the discovery of the CLA antigen numerous
human studies have confirmed the implication of circulating
CLA+, but not CLA-, memory T cells
in diverse T cell-mediated cutaneous diseases with various pathological
mechanisms. Circulating CLA+ T cells respond to
antigens, allergens, viruses, bacterial superantigens and drugs, with
the common feature of being involved in the physiopathological
mechanisms of distinct skin diseases such as dengue, leprosy,
drug-induced allergic reactions, or alopecia areata, to name a few
(Table I). Additionally, their phenotype in circulation has been
reported to correlate with the clinical activity and response to
treatment of cutaneous diseases.46
CLA+ T cells in AD
AD is characterized by a compromised skin barrier, abnormal cutaneous
immune responses, altered microbiota, and intense pruritus.
Translational knowledge derived from the efficacy and mechanism of
targeted therapies in AD patients has allowed identification of key
disease pathways that are in the basis of those abnormalities such as
CD4+ memory T cell-derived cytokines IL-13, IL-4,
IL-31 and IL-22.47,48 CLA+ T cells
are abundant in lesional skin31 and are related to
different aspects of AD, including clinical features, response to
treatment, and biomarkers (Figure 1).
CLA+ T cells in the clinical context of the
AD patient
Due to their homing/de-homing capacities between peripheral blood and
skin, circulating CLA+ T cells reflect cutaneous
abnormalities present in AD lesions (Figure 1).32Circulating CD4+ CLA+ and
CD8+ CLA+ T cells express increased
levels of CD25, CD40 ligand, HLA-DR and ICOS,33,49,50and after being purified from blood these cells continue to proliferate
spontaneously due to their in vivo activation phenotype in AD.
Additionally, long term T-cell HLA-DR activation in skin-homing cells is
increased in adults with AD compared to psoriasis patients or
controls.50 Circulating CD4+ and
CD8+ CLA+ T cells express the major
type 2 cytokines IL-4, IL-5, and IL-13,51 as well as,
IL-9, IL-17A, IL-21 IL-22, IL-31, IFN-γ, TNF-α, and
GM-CSF.52–55
CLA+ T cells contribute to type 2 immune response by
induction of IgE production by B cells and enhance eosinophil
survival.33,49,56 Production of IFN-γ by skin-homing T
cells is one of the main mechanisms of eczema formation due to
keratinocyte apoptosis. IFN-γ is mainly induced by IL-12, an important
mediator for the direction of the immune response towards IFN-γ
production. IL-12 is produced by keratinocytes and dendritic cells in
the microenvironment.57,58
Patients with AD showed increased frequencies of CLA expression and
selective CLA+ Th2/Tc2 and Th22/Tc22 expansion,
accompanied by selective CLA+ Th1/Tc1 reduction in
blood.53 Focusing on memory subsets, applying CLA
positivity classification, AD immune activation involves not only of
CLA+ T cells but also of CLA- or
’systemic’ T-cell subset. Compared to psoriasis, another inflammatory
skin disease,59 ‘systemic’/CLA- and
more prominently CLA+CD45RO+CCR7+ central memory
(Tcm) and CLA+CD45RO+CCR7- effector memory
(Tem) T cells were significantly more activated in AD
patients.50 Additionally, frequencies of
IL-13-producing CLA+ T cells and circulating
CLA+ Tem and Tcm cells
significantly correlated with AD severity and total IgE levels in serum
of AD patients, exemplifying how CLA+ frequencies may
reflect several disease aspects. The relatively easy access to
CLA+ T cells from peripheral blood provides less
invasive, translational diagnostic approach, that might be particularly
beneficial in certain populations, including children with AD, in whom
skin sampling may pose a great challenge.52 One such
blood phenotyping study comparing adults and children with AD showed
that in young children of less than 5 years old there is a dominant
signature of CLA+ Th2 cells, with
CLA+ Th1 reductions, while other immune changes build
up with time and disease chronicity.52 These results
point to the Th2 dominance in early AD, and support the importance of
addressing this immune axis when treating young populations.
Exacerbations of AD are occasionally associated with exogenous
environmental triggers.60 The defective skin barrier
prompts allergen/antigen penetration leading to specific responses of
cutaneous T lymphocytes. The response to allergens such as house dust
mite (HDM) is restricted to CLA+ T cells in
AD.49 A recent study has shown that the T-cell
receptor (TCR) repertoire of circulating allergen-specific
CLA+, but no CLA-, T cells have a
large overlap with this found in the infiltrated T cells of AD lesions
for the same patient.61
Epigenetic modifications have been suggested as possible contributors to
AD pathogenesis.62,63 Examples include increased DNA
methylation in the interleukin 4 receptor gene (IL4R ) or reduced
methylation in the thymic stromal lymphopoietin (TSLP ) promoter,
among others. Acevedo et al. showed that in AD patients,
CLA+ memory CD4+ T cells are
characterized by dysregulated epigenetic signatures affecting key
cytokine signaling pathways, such as reduced DNA methylation in theIL13 promoter that may account for the augmented ability of this
T-cell subset to produce IL-13.31 Altogether these
data suggest that CLA+ T cells play a central role in
the initiation and perpetuation of AD.64
S. aureus and CLA+ T cell interaction
in AD
S. aureus colonizes approximately 90% AD lesional and
non-lesional skin compared to only 10% of healthy
subjects65 and is linked to AD flare
up.66 S. aureus is involved in microbial
dysbiosis, skin barrier abnormalities and T cell-mediated
inflammation.67 It has been recently reported thatS. aureus- colonized AD patients have a distinct phenotype and
endotype with more severe disease.68 SEB superantigen
(Sag) is the most prevalent in AD69 and it is
associated with disease severity.70 Application of SEB
to intact AD skin induces dermatitis.71 There is a
strong mechanistic association between Sags and CLA+ T
cells, since S. aureus -reactive TCR Vβ skewing is found
preferentially in circulating CD4+ and
CD8+ CLA+ T cells from AD patients
and not controls,72,73 and an increased percentage of
CLA+ T cells bearing TCR Vβ for S. aureus Sags
is found in children with AD.74
Sags, compared to conventional antigens, induce T-cell expression of CLA
via an IL-12 dependent mechanism14 and contribute to
AD skin inflammation by activating large numbers of lesional T cells.
This process is important in increasing the population of memory T cells
that are capable of efficient extravasation to skin. These mechanisms
may act to maintain continuous T-cell activation in the skin and thus
perpetuate AD lesions even when the initiating allergen cannot be
demonstrated or absent from the current environment. In a coculture
model between circulating memory T cells and autologous epidermal cells
from AD lesions, SEB induced preferential activation of
CLA+, rather than CLA-, T cells
leading to broad production of T-cell-derived mediators present in AD
lesions (IL-13, IL-4, IL-17A, IL-22, CCL17 and CCL22), with IL-13 as one
of the highest produced Th2 cytokine and the only one that positively
correlated with patients’ eczema area and severity index (EASI), plasma
levels of CCL17 and IgE against S. aureus, and CCL26 mRNA
expression in cutaneous lesions (Figure 2).75 α-toxin
has also been reported to induce an enhanced IL-22 secretion by
peripheral blood mononuclear cells and CD4+ T cells
from AD patients compared to patients with psoriasis and
controls.76
CLA+ T cell relationship with AD biomarkers
and targeted therapies
While AD diagnosis is still mostly based on clinical criteria, there is
an ongoing search for reproducible, minimally invasive, reliable, and
valid biomarkers.21,77 Over 100 different markers have
been suggested as biomarkers in AD. The most reliable biomarker reported
is serum CCL17.21
The CLA+ T cells and CCL17 functions are related
mechanisms in AD. CCR4 is a receptor for CCL17 preferentially expressed
on circulating CLA+ CD4+ memory T
cells22 and Treg,78and CLA+ memory Th2 cells from AD patients selectively
migrate to human skin grafts transplanted onto SCID mice in response to
CCR4.23 Recent clinical data in children and adults
highlight CCL17 as a potential biomarker. Two independent pediatric
studies have shown that increased levels of skin CCL17 may predict AD
development in infancy.79,80 It may be hypothesized
that since children present a preferential Th2 response in
CLA+ T cells,4 the link between skin
CCL17 and AD development in these population, is in line with the
pathological role of CLA+ T cells in AD. In addition,
in adults a recent phase 1b study have shown that the oral
CCR4-antagonist RPT193 led to clinical improvement in moderate-to-severe
AD.81 On the other hand, the CCL27 that is a
CLA+ T cells attracting chemokine, has been shown to
be increased in the stratum corneum and associated with disease severity
in pediatric AD82. In adults, stratum corneum CCL27
also constitutes a biomarker of response to
nemolizumab.83
One potential issue for biomarkers in AD is that they differ among
diverse populations. Circulating CLA+ T cells have
been shown to correlate with AD immune skewing across ages and
ethnicities, and thus their applicability is not limited by disease
chronicity and/or patient demographics. Other suggested biomarkers
include E-selectin, CCL22/MDC (macrophage-derived chemokine), lactate
dehydrogenase (LDH), IL-18, IL-13, among others.84Serum IgE, commonly measured in AD patients, was suggested as a disease
biomarker, however it is only moderately correlated with AD severity,
and while CLA is applicable in both intrinsic (normal IgE levels) and
extrinsic (high IgE levels) AD patients, IgE measures and correlations
with disease severity are mainly relevant in extrinsic AD
patients,85 a fact that limits its use as a biomarker.
Another important feature of a biomarker is its ability to predict and
monitor therapeutic responses. The fully human monoclonal IgG4 antibody
dupilumab was shown to improve clinical, molecular and barrier measures
in moderate-to-severe AD patients. Bakker et al. showed that while their
relative proportion remains unchanged, there was a significant reduction
in the proliferation (Ki67 positivity) and decrease in production of
IL-4, IL-5, IL-13, and IL-22 before and during treatment with dupilumab,
limited to circulating CLA+, but not
CLA-, CD4+ T cells, supporting
CLA+ T-cell responses as a surrogate measure to
dupilumab efficacy.86,87
As mentioned above, another consideration is the accessibility of
(obtaining) the biomarker (blood, skin, tape stripping etc.), along with
the requisite for repeated sampling. Biomarkers obtained from tape
stripping or skin biopsies, as well as biomarkers that correlate with AD
comorbidities, were investigated.88 The fact that
CLA+ T cells are effortlessly extracted from
peripheral blood tests puts them under the category of minimally
invasive biomarkers,21 and reinforces their potential
as disease biomarkers in AD.
The OX40-OX40L interaction is involved in long-term and optimal cell
activation of CD4 T cells89 and OX4O signaling favors
expansion and survival of Th2 cells.90 OX40 is also
highly expressed by CLA+ CD45RO+CD4+ T cells in AD patients.91 The
OX40-OX40L axis has recently attracted attention in AD due to the
improvements shown in AD patients for both an anti-OX40 depleting
antibody (KHK4083)92 and a non-depleting monoclonal
antibody (Mab) (amlitelimab) that binds to OX40L present on antigen
presenting cells (SAR445229).93
IL-31 is a neuroimmune cytokine that was originally described as mainly
produced by CLA+ memory T cells in
AD.94,95 Although there is an anti-IL31RA Mab in phase
III for AD, the production of IL-31 and its relationship with the
clinical status of the patients has not been characterized. A recent
study has shown for the first time that in AD patients producing IL-31
by HDM-activated CLA+ memory T cells, IL-31 directly
correlated with patients’ pruritus intensity and plasma levels of CCL27
and periostin (Figure 3). Additionally, it was suggested that plasma
levels of HDM-specific IgE may stratify moderate-to-severe AD patients
and hopefully be useful for identifying patients more probable to be
responders for IL-31-directed therapies.96
Supported by proteomic97 and transcriptomic
studies,98 as well as, differentiated responses to
Th2-targeted therapies, and similarly to asthma, Th2 high and Th2 low
endotypes have been hypothesized. A recent coculture model defined the
SEB-CLA+ memory T-cell-IL-13 axis to functionally
distinguish Th2 high and Th2 low responders within a clinically
homogeneous adult moderate-to-severe AD population. Contrary to Th2 high
group, Th2 low group mainly produced IL-17A, IL-22 and IFN-γ and IL-13
response did not correlate with EASI, plasma levels of CCL17 andS. aureus -specific IgE, and CCL26 mRNA expression from cutaneous
lesions.75
Conclusions
Translational research has bridged basic science with clinically
relevant mechanisms of AD, and provided a rational for targeted
therapies in AD offering an integrated pathological
view.99 Current state of the art on the role played by
circulating CLA+ T cells in AD goes beyond their
skin-homing capacities and describe an integrative perspective of AD
pathophysiology. The abnormal Th2 responses found in AD is clearly
represented by CLA+ T cells and integrated in disease
pathology. Although some ILC2 cells express CLA, their role in adult
moderate-to-severe AD is a complex matter, since ILC2 need to be
activated by epithelial cytokines (alarmins) to induce type 2 immune
response and directed therapies against TLSP, IL-25, IL-33 and IL-1α
have not demonstrated clinical efficacy.48
In the clinical context of the patients, to highlight that in pediatric
patients CCL17 is a biomarker of AD severity progression where IL-4 and
IL-13 response is mainly present in CLA+, but not
CLA-, CD4+ T cells, and in adults
CCL17 is one of the best biomarkers for AD. CCL17 mechanistically
relates to CLA+ Th2 cells, since it binds to CCR4,
which is preferentially expressed on skin-homing T cells. As for the
relationship between S. aureus and AD, CLA+ T
cells preferentially express specific TCR Vβ for S. aureussuperantigens, such as SEB, leading to a broad cytokine-derived effector
function (Th2, Th1, Th17, Th22), being IL-13 the most abundant Th2
cytokine produced. Regarding pruritus and IL-31, CLA+T cells are providing better understanding between clinical context of
the patients and IL-31 production. From a therapeutic point of view,
CLA+ T cells are the subset of circulating memory T
cells that reflects early effects of dupilumab on Th2 and Th22 responses
in treated patients at week 4.86 All these different
perspectives suggest that CLA+ T cells are in the core
of AD pathogenesis, probably since studying SALT may provide a useful
surrogate for investigating the immune-inflammatory cutaneous
abnormalities present in AD.
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