REviEwS

T cells and the skin: from protective

immunity to inflammatory skin
disorders
Allen W. Ho and Thomas S. Kupper*
Abstract | Skin is our primary interface with the environment, and T cells are crucial for
orchestrating host immune responses against pathogenic microorganisms at this site.
Effective skin immune responses require the generation of antigen-specific effector T cells,
which home to cutaneous sites of injury or infection. Long-lasting immunity against future immune
challenges is mediated by memory T cells. Among the memory T cells found in skin are both
recirculating cells that transit between skin and blood and tissue-resident memory T (TRM) cells,
which remain in skin for long periods of time and mediate durable protective immunity. These
TRM cells also appear to drive many inflammatory diseases of skin. Here, we consider how a better
understanding of cutaneous T cell responses can aid in the development of effective new
therapies for immune-mediated cutaneous diseases.

Barrier tissues like skin are under constant siege
from an environment in which physical, chemical
and biological threats are abundant and ubiquitous.
Experimental studies of immune cells isolated from
human blood or from secondary lymphoid tissues in
mice were once thought to be sufficient to provide a
comprehensive understanding of adaptive immune
memory. However, recent findings have challenged
this paradigm. It has been estimated that at least as
many memory T cells exist in peripheral non-lymphoid
tissues as in secondary lymphoid tissues at any given
time, either as transient or more permanent residents1.
Furthermore, these tissue-dwelling T cells have very
different properties from the T cells found in blood
and lymph nodes. In this Review, we focus on the
T cell responses that develop in response to infections
or following antigen encounter in the skin2–4. Adult
human skin is home to abundant populations of mem-
ory αβ T cells, dendritic cells (DCs) and macrophages,
as well as lesser numbers of natural killer (NK) cells,
γδ T cells and innate lymphoid cells (ILCs)4,5 (Fig. 1).
Although effector and memory T cells coordinate
cutaneous immune responses against microorganisms
and cancer, aberrant or inappropriate T cell activation
Department of Dermatology, against innocuous or auto-antigens can lead to chronic
Brigham and Women’s inflammatory disorders of skin. Here, we discuss adap-
Hospital, Harvard Medical
School, Boston, MA, USA.
tive immune responses in the skin, particularly those
mediated by T cells that dwell in skin for varying
*e-mail: tkupper@
bwh.harvard.edu periods of time, and discuss the role of these cells in
https://doi.org/10.1038/ several immune-mediated dermatological diseases
s41577-019-0162-3 afflicting humans.
Skin T cell responses
Generation of effector T cell responses in skin. Skin is
a formidable physical barrier, and many of its intrinsic
cells contribute to this property — keratinocytes differ-
entiate and form the impermeable stratum corneum6,
while fibroblasts produce collagens, elastin and other
glycoproteins that give the dermis its toughness and
resilience7. Additionally, nearly every type of skin cell
can, upon stimulation, produce chemokines, cytokines
and other inflammatory mediators that activate cells of
the innate and adaptive immune systems and promote
leukocyte recruitment from blood4,5,8. Trauma to the epi-
dermis, infection or exposure to ultraviolet radiation can
activate skin cells, typically via the NF-κB-dependent
and MAP kinase-dependent pathways4,5,8–10. Innate
immune activation of dermal DCs leads to their matu­
ration into powerful antigen-presenting cells. Mature
DCs migrate through afferent lymphatics to the draining
lymph nodes, where they can activate naive T cells or
recirculating central memory T cells. Activated DCs can
also activate recruited or tissue-resident T cells in the
skin11. Episodic recruitment of T cells and other leuko-
cytes into inflamed or injured skin occurs many times
each day5,12 (Fig. 1).
Adult skin contains large populations of memory
T cells that are phenotypically, functionally and clonally
diverse13–15. Memory T cells are, by definition, derived
from naive T cells that have undergone multiple rounds
of clonal expansion16. Skin-tropic effector T cell clones
are generated from naive T cell precursors that have
been activated by antigen-presenting DCs in lymph

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CD8+ DETC
LC TRM cell (mouse)
Stratum
corneum
Stratum
granulosum

Epidermis
Epidermis
Stratum
spinosum

Stratum Melanocyte
basale
CD4+
γδ T cell TRM cell CD8+
TRM cell
Papillary ILC
dermis DC

NK cell
Dermis
Macrophage

Fibroblast
Reticular
dermis
Recirculating
memory CD4+
T cell
Recirculating Afferent
Blood memory CD8+
vessel T cell lymphatic
vessel

Fig. 1 | The structure of the skin contributes to its immune functions. The epidermis is composed of layers of
increasingly well-differentiated keratinocytes, while the dermis includes superficial (papillary) and deep (reticular) layers.
Cutaneous immunology has benefited heavily from the study of murine skin as a model organism; however, key differences
between human and mouse skin exist. The most prevalent immune cell types that populate human epidermis are
Langerhans cells (LCs) and CD8+ tissue-resident memory T (TRM) cells. The murine epidermis contains dendritic epidermal
T cells (DETCs), which are absent in human epidermis. Both the mouse and human dermis are populated by dendritic cells
(DCs), macrophages, innate lymphoid cells (ILCs), natural killer (NK) cells and CD8+ TRM cells. The dermis also provides
structural support for the skin and, as such, consists of fibroblasts and connective tissue. In murine dermis, γδ T cells play a
prominent role in the production of IL-17 , while in human skin αβ T cells are responsible. The functional coordination of
these cellular mediators results in effective immune responses and a subsequent return to immune homeostasis.

nodes that drain the skin11,14. Clonally expanded effec-
tor T cells generated under these conditions traffic to
skin, accumulating in highest abundance at the site of
initial antigen encounter (Fig. 2). However, these cells
also accumulate in non-inflamed skin, albeit in lower
numbers17. The effector T cell populations that are gen-
erated during an acute immune response are far more
numerous than the memory T cell populations that
survive long term in the skin, but the precise relation-
ship between these populations is unclear18. One model
suggests that memory T cells are a distinct lineage that
derive from an early activated T cell subpopulation
without going through effector T cell expansion18,19. By
contrast, another model suggests that memory T cells
have gone through considerable clonal expansion and
derive stochastically from a subset of surviving effector
T cells3,20,21. The heterogeneity of memory T cells bears
emphasizing, not just with regards to their effector func-
tions and cytokine profiles but also with regards to their
trafficking properties22.
Generation of skin-homing T cells. It has been more
than 20 years since the initial observation that anti-
gen encountered through skin leads to the generation
of skin-homing T cells, whereas antigen encountered
through the gastrointestinal tract generates gut-homing
T cells23–25. Given that the scope of this Review is lim-
ited to cutaneous T cell immunity, we focus on the
generation of skin-homing T cells. While the features
in the tissue-draining lymph node microenvironment
that imprint T cells with tissue-homing properties are
not completely understood, many key changes appear
within the first few T cell divisions26. In skin-draining
lymph nodes, uniquely glycosylated ligands for
E-selectin and P-selectin (including cutaneous lympho­
cyte antigen (CLA)) are upregulated by activated
T cells in association with α(1,3) fucosyltransferases5,26.
In addition, this same population of activated T cells
acquires expression of a set of chemokine receptors,
including CC-chemokine receptor 4 (CCR4), CCR8
and CCR10 (ref.5). These E-selectin ligands in concert

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Priming phase Effector phase Memory phase

Lymphatic (3–10 days) (>25 days)

↓ T-bet
S1PR1, ↓ EOMES
CCR7 CD8+
Memory ↓ S1PR1
Circulating TRM cell
precursor ↓ SELL
TM cell Teff cell Teff cell TGFβ,
IL-15 ↑ RUNX3
↑ FAB4/FAB5
CLA ↑ CD69
↑ CD103
APC ↑ BCL-2
CD4+
↑ HOBIT
ESL, TRM cell
PSL, APC (mouse)
Activated T cell ↑ BLIMP1
CCR4,
Secondary CCR8, Pathogens (mouse)
lymphoid tissue CCR10

Skin

Blood

Fig. 2 | The generation and maintenance of cutaneous tissue-resident memory T cells. Following microbial invasion,
antigen-presenting cells (APCs) migrate from the site of insult to the secondary lymphoid tissues via afferent lymphatic
vessels. T cell priming occurs within the secondary lymphoid tissue, resulting in the generation of effector T cells (Teff cells,
which include memory T (TM) cell precursors) that travel to the site of inflammation. This pool of Teff cells eradicates the
infection, concluding the effector phase of an immune response, which typically lasts 3–10 days. Following microbial
clearance, the majority of Teff cells die, while subsets of T cells become recirculating memory cells or are maintained in the
tissue as tissue-resident memory T (TRM) cells. Recirculating memory T cells leave skin in response to gradients of
sphingosine-1-phosphate and CC-chemokine ligand 21 (CCL21), which bind to sphingosine-1-phosphate receptor 1 (S1PR1)
and CC-chemokine receptor 7 (CCR7), respectively. The generation of TRM cells results from a specific transcriptional
signature that has been characterized. TM cells are defined as cells that persist in the absence of inflammation or infection,
usually >25 days after the original exposure. BLIMP1, B lymphocyte-induced maturation protein 1; CL A , cutaneous
lymphocyte antigen; ESL , E-selectin; HOBIT, homologue of BLIMP1 in T cells; PSL , P-selectin; RUNX3, runt-related
transcription factor 3.

with skin-specific chemokine receptors and leukocyte
integrins allow for the tethering and arrest of these
T cells in dermal post-capillary venules, and this results
in their extravasation into tissue5 (Fig. 2). Once on the
abluminal side of the vessel, T cells respond to chemo-
tactic gradients within the skin and migrate to the site
of injury or infection5. Vitamins A and D have been
shown to regulate T cell homing to gut and cutane-
ous tissues, respectively, via modulation of chemokine
receptors and selectins or vascular adhesion molecule
ligands27,28. However, while the role of vitamin A in
imprinting gut T cell homing by inducing β7 integrin
and CCR9 is broadly accepted, the role of vitamin D
in imprinting T cells with a skin-homing programme
is more controversial. The active metabolite of vitamin
D3, 1α,25-dihydroxyvitamin D3, was shown to induce
CCR10 expression in human T cells and to a much lower
degree in mouse T cells29. However, only a minority of
skin-homing T cells bear CCR10, and T cell expression
of the skin-homing chemokine CCR8 is independent of
vitamin D; rather, keratinocyte-derived soluble factors
lead to T cell expression of CCR8 (ref.30). Furthermore,
1α,25-dihydroxyvitamin D3 inhibits expression of CLA
and, in parallel, functional E-selectin ligand, resulting in
less skin infiltration of effector CD4+ T cells31. Although
skin-homing molecules on memory T cells are essen-
tial for entry into non-inflamed skin, active inflam-
mation makes T cell entry into skin more permissive.
Signalling via G protein-coupled receptors, including
CXC-chemokine receptor 3 (CXCR3), play an inte-
gral role in cutaneous T cell infiltration in this setting.
Inflamed skin expresses high levels of CXC-chemokine
ligand 9 (CXCL9) and CXCL10, which leads to the
recruitment of CXCR3+ T cells to the sites of cutaneous
inflammation32–36. However, CXCR3 is not absolutely
required for this process, as CXCR3-deficient CD8+
T cells can be found in the skin during cutaneous vac-
cinia virus (VACV) infection36, suggesting that CXCR3-
independent recruitment mechanisms also exist. In
addition, although the recruitment of effector CD8+
T cells to the lung and vagina requires IFNγ-producing
CD4+ T cells35,37, virus-specific tissue-resident memory T
(TRM) cells develop and persist in the skin in the absence
of CD4+ T cells17.
Skin infection preferentially generates skin-homing
effector T cells in draining lymph nodes, but there is evi-
dence for leakiness in the process. After VACV infec-
tion of skin, CD8+ T cells upregulate E-selectin ligand
within five cell divisions, but a subset of proliferating
CD8+ cells exit the lymph node after three cell divisions
and enter the mesenteric lymph nodes, where they
upregulate gut-homing molecules and are later detected
as α4β7 integrin-positive memory T cells in the gut26.
Blocking this early exit of proliferating cells from lymph
nodes using FTY720 (fingolimod) (an antagonist of
sphingosine-1-phosphate receptor 1 (S1PR1)) abrogates
this process entirely26,38. Thus, the adaptive immune sys-
tem hedges its bets by generating populations of effector

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T cells with more than one tissue tropism, allowing for
the possibility that the pathogen will be encountered
at a different environmental interface in the future.
Additional work done in a VACV skin infection model
showed that, while most CD8+ effector T  cells are
recruited to inflamed skin, other CD8+ effector T cells
enter uninflamed skin throughout the body with similar
kinetics17. The size of the effector CD8+ T cell population
in the skin peaks at 10 days after infection and declines
sharply thereafter17,39. Transcriptional profiling suggests
that the effector T cell gene expression profile changes to
a TRM cell profile at approximately day 25 post-challenge,
which then appears to persist indefinitely39,40 (Fig. 2).
Memory T cells provide immunosurveillance and
mediate a rapid response to future attacks from known
pathogens. Nearly two decades ago, it was proposed that
two populations of circulating human memory T cells
exist, each with different trafficking properties41,42.
Central memory T (TCM) cells, like naive T cells, express
CCR7 and CD62L and circulate between lymph nodes
and blood, while effector memory T (TEM) cells lack
CCR7 but express tissue-homing addressins, allowing
them to gain access to non-lymphoid peripheral tis-
sues43. This paradigm, though still useful, continues to
be modified substantially, as populations of T cells that
express either CCR7 or CD62L (but not both) have been
demonstrated15,42. More recently, cells with CCR7 and
CD62L that also express the skin-homing molecules
CLA and CCR4 have been identified42,44, indicating that
cells with TCM cell markers can enter peripheral tissues.
These skin-homing TCM cells can give rise to TRM cells in
skin16,44–46, and there is a subtype of cutaneous T cell lym-
phoma in which the malignant cells bear a skin-homing
TCM cell phenotype42,47 and recirculate between skin and
blood. In addition, skin-homing TEM cells that express
CCR7 have been shown to enter skin and then exit skin
via afferent lymphatics in response to CC-chemokine
ligand 21 (CCL21) gradients15,48 (Fig. 2).
Skin-resident T cells. In 2001, it was demonstrated
that, after the resolution of systemic viral infection,
T cells are detected and persist for long periods of time
in peripheral non-lymphoid tissues25,49–51. The term
skin-resident T cell first appeared in the early 2000s in
reference to memory T cells found in lesions of fixed
drug eruptions, which appear at the same location after
repeated exposure to the same drug52. In 2004, Boyman
et al. reported that non-lesional skin from patients
with psoriasis (but not normal control skin) developed
a psoriatic phenotype when grafted onto immuno­
compromised mice53, suggesting that pathogenic T cells
reside in normal-appearing adult skin. In 2006, a sem-
inal report by Clark et al. demonstrated that there were
roughly four times as many memory T cells in adult
human skin as there were in peripheral blood13. These
skin T cells were heterogeneous and retained potent
effector functions, with different subsets producing
IFNγ, IL-17 or IL-13 overexpressing a regulatory T
(Treg) cell phenotype13,54. More recently, the same group
described four distinct populations of memory T cells in
skin — a population of TCM cells, a population of migra-
tory memory T cells and two populations of TRM cells15.
Non-recirculating T RM  cells in human skin were
mostly CD4 + and CD69 + (ref. 15) . CD8 + T RM  cells
were mainly epidermal and expressed CD103, a ligand
for E-cadherin. A more rapidly recirculating popula-
tion of T cells that expressed CLA, CCR4, L-selectin
and CCR7 were identified as skin TCM cells, whereas a
more slowly recirculating population of skin T cells that
expressed CCR7 (but not L-selectin) were termed migra-
tory memory T (TMM) cells, and it was proposed that
these cells may be the direct precursors of TRM cells. As
TMM cells clearly recirculate, this may explain why multi-
ple discrete (that is, TRM cell-containing) skin lesions can
develop in both benign and malignant T cell-mediated
skin disorders15. It should be noted that TMM cells were
described previously by other groups as recirculat-
ing T cells that migrate from skin to lymph nodes via
afferent lymphatics23,48.
Resident memory T cells. T RM  cells are defined as
non-recirculating T cells that reside indefinitely in
peripheral tissues; they have been identified in nearly
every normal and diseased tissue of the body, including
in malignant tumours2,3,22,55–59. Although the transcrip-
tional profiles of TRM cells isolated from brain, lung,
skin and intestine differ slightly, there is a core gene
expression signature that seems to be retained39,40,60–62.
Common features are the downregulation of genes
encoding S1PR1, EOMES and CD62L and the upreg-
ulation of CD103 and various genes involved in adap-
tive immune responses and lipid metabolism39,40 (Fig. 2).
CD69 appears to be nearly universally expressed on
skin TRM cells, and it serves to interfere with the func-
tion of S1PR1, thereby making TRM cells unresponsive
to the sphingosine-1-phosphate gradients that normally
guide T cells to lymph nodes63. However, TRM cells in
other tissues do not express CD69 as faithfully as skin
TRM cells64,65, suggesting that caution should be used
in relying on this marker to define TRM cells. The tran-
scription factors that characterize TRM cells are also the
subject of some controversy — B lymphocyte-induced
maturation protein 1 (BLIMP; also known as PRDM1)
and the homologue of BLIMP1 in T cells (HOBIT; also
known as ZNF63) appear to be important for murine
TRM cells but not for human TRM cells. More recently,
runt-related transcription factor 3 (RUNX3) was identi-
fied as a necessary factor for tissue residence40,61,66 (Fig. 2).
It is unlikely that any single factor is sufficient to confer
tissue residency, and it is more likely that some redun-
dancy of factors ensures this property; these include the
above variables as well as dependence on lipid uptake
and metabolism, IL-15 and transforming growth
factor-β (TGFβ)39,62,67–69.
TRM cells appear to survive, in part, by proliferating
in situ at a low level45,46. A current paradigm holds that
TRM cells cannot leave tissue and recirculate and can be
replaced by circulating T cells, with both circulating
TCM cells and TEM cells contributing16,44–46,70. Although
both TCM cells and TEM cells can become TRM cells16,44,70,
it is not known whether the TRM cell state represents ter-
minal differentiation. It was recently suggested that the
most proximal precursor to the TRM cells is the TMM cell15.
Whether this differentiation is unidirectional or whether
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TRM cells can occasionally revert back to TMM cells and
exit the skin is currently unknown15,16. Although a single
study demonstrated that the tissue microenvironment
could lead to the development of TCM cells or TEM cells
from gut-resident T cells upon reactivation71, the current
dogma based on more recent data is that TRM cells do not
de-differentiate22,45,46,70. For example, cutaneous TRM cells
appear to proliferate in situ but do not differentiate into
other memory T cell subsets nor leave the skin to recir-
culate45. TRM cells from other epithelial tissues such as
the uterine mucosa and lung behave similarly46,70. It is
not yet known whether epigenetic changes occur in
TRM cells that limit their developmental plasticity, and
this p
­ ossibility is the subject of much current interest.
Antiviral CD8+ TRM cells can protect the host by
directly killing virally infected cells72. In addition,
TRM cell activation can induce a generalized antiviral
state in skin, promoting the release of type I interferons
by keratinocytes and other skin cells56,73,74. As already
mentioned, skin CD8+ TRM cells typically express CD103
and are localized to the epidermis, but CD103–CD8+
TRM cells have been reported32,33,75. By contrast, skin
CD4+ TRM cells are less well characterized and appear to
localize in the papillary dermis13,15. CD4+ TRM cells spe-
cific for herpes simplex virus (HSV) (T helper 1 (TH1)
cell-like), Leishmania spp. (TH1 cell-like) and Candida
albicans (TH17 cell-like) have all been described, and
their expression of CD69 is high, while their expression
of CD103 is variable76–78. They have been shown to either
cluster near hair follicles or to be more evenly distrib-
uted; these differences may be dependent on the model
or pathogen15,76,79,80. Like CD8+ TRM cells, CD4+ TRM cells
can be rapidly activated by pathogen re-challenge and
promote more rapid clearance of the pathogen from
skin76 (Fig. 2). There is also evidence that, in addition to
CD8+ TRM cells, local infection generates high levels of
CD4+ TRM cells at the site of infection and lower levels
throughout the entire skin, thus providing global protec-
tion76. The question of whether TRM cells alone are suffi-
cient to protect against infection is also model-specific
and pathogen-specific. For the VACV system, CD8+
T cells alone without antibody or circulating T cells are
sufficient for full protection17, whereas for Leishmania
spp. infection, circulating T  cells are required to
augment T RM  cell-mediated protective responses 77.
Regardless of the specific infection, the posting of potent
antigen-specific TRM cells at sites where the host is most
likely to encounter the pathogen in the future represents
sound immunological planning.
Latent HSV infection provides an illustrative model
in which CD8+ TRM cells control active viral infection
even when inflammation and effector cell recruit-
ment from the blood have abated81,82. Cutaneous HSV
infection in mouse models results in the generation of
CD8+ TRM cells that remain millimetres from the site
of infection, providing long-lasting site-specific immune
surveillance68,78. Protection against recrudescent HSV
infection depends on HSV-specific TRM cells at the site
of prior infection; these TRM cells engage virus-infected
cells, are constrained to the epidermis and prolifer-
ate in situ45. Furthermore, the cutaneous TRM cells are
maintained as a stable population after recall32,45. These
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findings have also been extended to human skin. Even
months after HSV-2 infection of human genital skin,
HSV-2-specific CD8+ T cells are present at the dermal–
epidermal junction and are in contact with keratino­
cytes 83. Following cutaneous HSV-1 reactivation,
CD8+ T cells at the site of infection express the CD8αα
homodimer rather than the CD8αβ heterodimer84. HSV-
2-specific CD4+ T cells are retained at sites of HSV-2
reactivation for months after healing within the dermis85.
T cells in skin: of mice and men. Most work on the
real-time generation of TRM cells in skin after microbial
or viral infection has been performed in mice86. By the
time they reach adulthood, humans have lived for many
years in a pathogen-rich world and have accumulated
memory T cell clones that inhabit both lymphoid tissue
and peripheral barrier tissues87,88. By contrast, labora-
tory mice are kept under carefully controlled specific
pathogen-free (SPF) conditions and are typically exam-
ined at an early age — as such, they possess relatively few
memory T cells and far more naive T cells86. In skin, mice
are born with two unique populations of γδ T cells in the
dermis and epidermis89. Epidermal γδ T cells, also known
as dendritic epidermal T cells (DETCs), have a T cell
receptor (TCR) with a single antigenic specificity90 (Fig. 1).
They are generated in the thymus during embryonic
development and home to skin in utero91. Functionally,
they are thought to play a role in wound healing and
epidermal repair and may have an innate immune sig-
nalling function89,92–94. DETCs are sessile and do not
circulate out of the skin. Dermal γδ T cells are more
diverse with regard to antigen recognition and are
important as a first line of defence for a subset of patho-
gens95. Parabiosis experiments suggest that migration of
dermal γδ cells resembles that of human skin TMM cells,
with slow kinetics of recirculation out of skin96. Before
explicit or experimental antigenic challenge or infection,
comparatively few αβ T cells exist in mouse skin, and
many of these are recirculating Treg cells97. Unlike αβ
T cells, γδ T cells do not recognize peptides bound to
MHC molecules, and different subsets appear to have
different antigenic specificities94. In general, activating
ligands for γδ T cells are incompletely characterized but
include host stress proteins like MICA and NKG2B98.
In mouse skin, DETCs appear to respond to epidermal
stress antigens89, and dermal γδ cells produce abun-
dant IL-17 after C. albicans infection, application of
­imiquimod or injection of IL-23 (refs99–101).
Two recent studies suggest an intriguing explanation
for the abundance of γδ T cells over αβ T cells in the
epidermis and dermis of young mice kept in SPF condi-
tions. Mice infected with HSV developed HSV-specific
CD8+ T cells that assumed a dendritic morphology and
displaced local DETCs68. Similarly, mice infected with
C. albicans developed a large population of CD4+
TRM cells, which outnumbered dermal γδ cells and were
the predominant IL-17-producing cells on re-challenge76.
In a non-SPF world replete with pathogens, such encoun-
ters would likely happen repetitively over the life of
the mouse. Indeed, the density of skin γδ cells in mice
housed in pet stores or living in barns is diminished, and
αβ T cells are far more abundant, as are memory T cells
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in general102. The immune systems of these mice more
closely resemble those of adult humans, whereas those
of SPF mice resemble the immune systems of neonatal
humans102. One could speculate that skin γδ cells repre-
sent a primitive adaptive immune system that is replaced
by αβ TRM cells over time as the mouse encounters more
and more antigenic pathogens through skin.
CD1a and skin-specific T cell responses. Conventional
cutaneous T cell responses have been thought to require
T cell recognition of peptide antigens bound to MHC
complexes on the cell surface of antigen-presenting
cells. However, recent evidence has demonstrated that
T cells can respond to lipid antigens presented by CD1
molecules103. Mice do not express CD1a, CD1b and
CD1c, whereas human skin Langerhans cells (LCs)
constitutively express CD1a at high levels104. Subsets of
human dermal DCs also express CD1a, albeit at lower
levels104. In contrast to the limited repertoire of invar-
iant natural killer T (NKT) cells, the CD1a-specific
T cell repertoire contains diverse TCRs105,106. Many
CD1a-autoreactive T cells home to skin, where they pro-
duce IFNγ, IL-2 and IL-22 in response to CD1a–lipid
complexes on LCs107,108. Recent studies have suggested
a role for CD1a-autoreactive T cells in mediating cuta-
neous allergic and inflammatory responses109–111. For
example, in psoriatic skin lesions, there is an increased
number of CD1a-reactive T cells associated with higher
expression of mast cell-derived phospholipase A2
(PLA2); this can convert non-antigenic phosphatidic
acid-containing molecules into lysolipid neo-antigens
that can be accommodated by the groove of the CD1a
molecule109,110. Mice lack CD1a expression, and a trans-
genic mouse expressing the human CD1a transgene in
LCs showed exacerbated skin inflammation in response
to imiquimod-induced dermatitis, which models cer-
tain downstream events in psoriasis111. Furthermore,
both bee venom-allergic individuals and house dust
mite-allergic individuals have a higher frequency of
CD1a-reactive T cells that release IFNγ, GM-CSF and
IL-13 in response to PLA2, likely derived from autol-
ogous substrates110. While CD1a-autoreactive T cells
produce pro-inflammatory cytokines, the propensity
for IL-22 production by CD1a-autoreactive T cells in
healthy individuals suggests a possible immune home-
ostasis function in skin109. There is also evidence that
CD1 autoreactivity can serve an instructive or regulatory
role via crosstalk with CD1-expressing DCs112. The com-
plete role of CD1a-reactive T cells in human skin disease
remains to be elucidated.
The skin microbiota and T cell education. In recent
years, the importance of commensal microorganisms in
shaping the host immune system has become increas-
ingly clear. Across the 1.8 m2 of the skin surface of the
human body resides more than 1010 bacterial cells113.
Moreover, eukaryotic fungi and viruses are also abun-
dant114. The skin microbiome promotes both innate and
adaptive immune responses to limit pathogen invasion
and maintain homeostasis97,115. As part of their immune
modulatory role, skin commensals tune the function
of nearby T cells by stimulating increased DC IL-1α
production, which is followed by production of IL-17
and IFNγ from dermal T cells116. A recent study has
demonstrated that introduction of Staphylococcus epi-
dermidis to gnotobiotic mice restores the production
of IL-17A by T cells, indicating that S. epidermidis can
influence host defence as part of the skin commensal
microbiome. In this study, S. epidermis was the only
commensal species that increased the frequency of
CD8β+ T cells in the skin; these T cells reside in epi-
dermis and resemble TRM cells, enhance barrier immu-
nity and limit pathogen invasion117. It is not known how
many skin TRM cells are specific for antigens on commen-
sal organisms and whether this putative responsiveness
is modified by the activity of skin Treg cells.
Regulatory T cells in the skin
Barrier tissues also require mechanisms to regulate
and suppress inflammation 118–122. In human skin,
Treg cells have been described as a resident population
and shown to interact with fibroblasts and LCs in situ
in the absence of inflammation13,15,54,79,123. In peripheral
blood, most circulating Treg cells express skin-homing
markers, suggesting constitutive trafficking to skin124.
In mouse skin, a wave of Treg cells derived from the thymus
arises in early neonatal life in response to skin coloni-
zation with S. epidermidis, aiding in the establishment
of immune tolerance to commensals97. In a model of
cutaneous inducible ovalbumin expression, a population
of Treg cells remain in the skin following the resolution of
skin inflammation and express low levels of CD25
and other markers associated with memory T cells125.
However, inflammation-experienced Treg cells reverse
most of their activation-induced changes and lose their
suppressive ability over time126.
Advances in genomic technologies have provided
valuable tools to probe the diversity of tissue-resident
Treg cells. Single-cell RNA sequencing (scRNAseq) anal-
ysis of Treg cells from mouse colon and skin demonstrates
a shared core transcriptional signature, suggesting that
there may be a shared general residency programme in
barrier tissues127. Another recent study combined scR-
NAseq with TCR analysis of Treg cells from mouse colon
and demonstrated that Treg cells sharing the same TCR
clonotype display similar transcriptional identities, sug-
gesting that shared antigenic specificity may drive these
Treg cells to the same anatomical location and maintain
them there128. However, tissue-specific signals may shape
the more nuanced transcriptional differences between
tissue-specific Treg cells. Integrating scRNAseq with assay
for transposase-accessible chromatin using sequencing
(ATACseq) to provide insight into chromatin accessibil-
ity of Treg cells isolated from the non-lymphoid tissues
— visceral adipose tissue, colon and muscle — revealed
that chromatin accessibility and gene expression often
did not align, with a number of open chromatin regions
already accessible in the spleen129. It is tempting to specu-
late that this mechanism may permit more rapid changes
in gene expression within tissues as Treg cells respond to
various tissue-specific stimuli.
Recent work has also focused on the mechanisms by
which Treg cells traffic to the skin. CCR4 has been a focus
of study, as both circulating124 and cutaneous54 Treg cells
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 Reviews

Table 1 | Selected therapies that target pathogenic cutaneous T cells the epidermal growth factor receptor pathway, similar
to Treg cells involved in lung repair132.
Therapy mode of action Disease
Dupilumab Inhibits IL-4 and IL-13 Atopic dermatitis T cells in skin diseases
signalling The prevalence of T cell-mediated skin diseases and
Ixekizumab Neutralizes IL-17A Psoriasis their frequent responsiveness to skin-directed therapy
Secukinumab Neutralizes IL-17A Psoriasis have led to speculation that many or most of these dis-
eases involve TRM cells. A comprehensive discussion of
Ustekinumab Neutralizes p40 subunit Psoriasis
of IL-12 and IL-23 all T cell-mediated skin diseases is outside the scope
of this Review, but below we discuss some of the more
Tildrakizumab Neutralizes p19 subunit Psoriasis
of IL-23 common diseases, including psoriasis, atopic dermatitis,
alopecia areata and vitiligo.
Guselkumab Neutralizes p19 subunit Psoriasis
of IL-23
T cells in psoriasis. Psoriasis is a disease that afflicts
Adalimumab Neutralizes TNF • Psoriasis
2–4% of the world’s population. It is rarely fatal but can
• Hidradenitis suppurativa
• Pyoderma gangrenosum (off-label) be associated with crippling joint disease as well as a
pro-inflammatory metabolic syndrome that increases
Infliximab Neutralizes TNF • Psoriasis
• Hidradenitis suppurativa the risk of death from coronary artery disease, stroke
• Pyoderma gangrenosum (off-label) and adult-onset diabetes134,135. An immune aetiology for
Etanercept Inhibits TNF signalling • Psoriasis psoriasis had been suspected ever since the identification
• Hidradenitis suppurativa of HLA-Cw6 as a high-risk allele136,137. A seminal study
• Pyoderma gangrenosum (off-label) showed that denileukin diftitox (a drug comprising the
Tofacitinib JAK1 and JAK3 inhibitor • Psoriasis (off-label) ligand-binding portion of the IL-2R molecule fused to
• Alopecia areata (off-label) diphtheria toxin A subunit) cleared disease symptoms
• Vitiligo (off-label) in a significant number of patients with psoriasis, con-
• Atopic dermatitis (off-label) firming that T cells are necessary for clinical psoriasis138.
• Dermatomyositis (off-label)
Patients with psoriasis also responded impressively
Ruxolitinib JAK1 and JAK3 inhibitor • Psoriasis (off-label) to tumour necrosis factor (TNF) inhibitors, which
• Alopecia areata (off-label)
• Vitiligo (off-label) became the drug of choice for psoriasis for many years135
• Atopic dermatitis (off-label) (Table 1). Around the time that ustekinumab, an anti-
• Dermatomyositis (off-label) body directed at the shared p40 chain of IL-12 and IL-23,
The mechanistic dissection of the immunopathogenesis of inflammatory cutaneous disorders began to show impressive clinical effects in psoriasis, sev-
has resulted in highly targeted and effective therapies. As tissue-resident memory T (TRM) cell eral groups identified IL-17 as a key cytokine in psoriasis,
immunobiology becomes better understood, novel therapeutics that specifically eradicate
pathogenic TRM cells may lead to durable responses in a number of chronic, inflammatory skin and TH17 cells and IL-17-producing CD8+ T cells (Tc17)
diseases. JAK , Janus-activated kinase; TNF, tumour necrosis factor. cells were shown to be abundant in lesional skin139–141.
It is well known that IL-23 is critical for the expansion
express CCR4. In mice, CCR4-deficient Treg cells failed of IL-17-producing T cells, and recent clinical studies
to reconstitute the cutaneous Treg cell compartment130. using therapeutic antibodies against IL-17 or IL-23 (p19
Mouse Treg cells have been found to localize to hair fol- subunit) have shown the most dramatic improvement to
licles79,115, and in a mouse model of skin-specific hair date in psoriasis142–146 (Fig. 3). A number of studies have
follicle morphogenesis arrest, the skin Treg cell popula- shown that a single-nucleotide polymorphism in IL-23R
tion was reduced without affecting Treg cell populations is linked to human autoimmune disease147–151, raising the
in other tissues. Furthermore, the skin of neonatal SPF issue of whether IL-23R does something more than sim-
mice produces high amounts of CCL20, and its receptor, ply expand the number of TH17 cells. Regulatory network
CCR6, is enriched on cutaneous Treg cells. Accordingly, analysis suggests that IL-23 promotes the differentiation
adoptive transfer experiments demonstrated that CCR6- of pathogenic TH17 cells by inducing the phosphory­
deficient Treg cells were at a competitive disadvantage in lation of FOXO1 and unabated expression of IL-23R152.
reconstituting the skin T cell compartment115. CCL20 Thus, while TH17 cells can be expanded by IL-21, it is
mRNA expression is also increased in human fetal exposure to IL-23 that appears to be critical for evoking
skin explants exposed to cutaneous commensals and the pathogenic potential in TH17 cells. Transcriptomic
bacterial components115. analyses have elucidated transcriptional and regulatory
Very recently, Treg cells have been implicated in a networks that mediate TH17 cell differentiation and func-
number of non-immunological functions relevant tion152,153. Thus, the prediction would be that pharma-
to cutaneous biology. Cutaneous Treg cells have been cological inhibition of IL-23 would lead to even more
shown to regulate cutaneous wound healing and, in durable responses than inhibition of IL-17 and may not
some models, to modulate hair follicle stem cells131–133. result in the paradoxical worsening of inflammatory
Accordingly, skin Treg cells accumulate in large numbers bowel disease seen with IL-17 inhibitors154,155.
at the affected site soon after a wound injury in skin. Psoriasis has a predilection for always return-
These Treg cells have an activated phenotype and limit ing in the same anatomical location, and a recent
IFNγ production by T cells and inflammatory macro­ study showed that healed psoriasis lesions cleared by
phages in wounds133. The Treg cells involved in cuta­ anti-TNF therapy contained TRM cell clones, several of
neous wound healing were shown to be dependent on which shared the same amino acid sequence in the third

Nature Reviews | Immunology

Reviews

Epidermis

Stimulus (trauma, infections,

medication or release of
cytokines and/or IL-1α)

TNF Tc17 cell

(TRM cell)
Autoantigens
LL-37/cathelicidin, Resident
ADAMTSL5, TH17 cell
PLA2G4D
IL-6, IL-17,
IL-23, IL-21, Epidermal remodelling
TGFβ IL-22 and/or keratinocyte
Dendritic cell
release of proinflammatory
cytokines

VEGF,
T17 cell FGF

Pro-inflammatory Angiogenesis
cycle
IL-23,
IL-6, T17 cell
TGFβ
Neutrophil
Secondary lymphoid tissue recruitment

Fig. 3 | T cells in the pathogenesis of psoriasis. After an initial stimulus that results in the activation of the innate immune
system and release of putative auto-antigens, activated dendritic cells drive the activation and expansion of IL-17+
tissue-resident memory (TRM) cells (T17 cells), which include both IL-17-producing CD8+ T cells (Tc17 cells) and T helper 17
(TH17) cells. IL-23 is critical for the expansion and the differentiation of pathogenic T17 cells. The development of
pathogenic T17 cells leads to the release of a pro-inflammatory cytokine milieu resulting in the key features of psoriasis
including neutrophil microabscesses, keratinocyte proliferation, further lymphocytic infiltration and angiogenesis. IL-22,
produced by either Tc17 cells or TH22 cells, also drives epidermal proliferation. TNF, tumour necrosis factor.

complementarity-determining region (CDR3) of their
TCR156. Because anti-TNF treatment will suppress the
activity of TRM cells but cannot dislodge them from
the tissue, it is likely that these antigen-specific TRM cells
that remain at the same site will be activated in the
future. However, the antigen specificity of these CD8+ αβ
T cells is unknown. Although mouse models of psoriasis,
whether mediated by topical imiquimod application or
IL-23 injection, exclusively involve γδ T cells produc-
ing IL-17, these cells appear to be a small minority in
human skin, whether normal or psoriatic. As shown by
high-throughput sequencing of TCRs, γδ cells make
up <3% of T cells in psoriatic skin and are not observed
at all in healed psoriatic lesions156. The elucidation of the
immune pathophysiology of psoriasis remains the most
complete and comprehensive body of work on a human
autoimmune disease.
T cells in atopic dermatitis. Atopic dermatitis (AD) is
the most common chronic inflammatory skin disease,
with the lifetime prevalence reaching 10–20% in devel-
oped countries157. The diagnosis of AD relies heavily
on clinical features, as there are no precise consensus
laboratory or histological findings158,159. Eczematous,
cutaneous lesions in a characteristic distribution, which
changes depending on age of onset, and severe pruri-
tus are hallmarks of disease158,159. Moreover, AD is often
associated with different atopic and allergic comor-
bidities, including food allergies, allergic rhinitis and
asthma, all disorders associated with overdeveloped
type 2 immunity158,159. Though the precise pathogenesis
of AD continues to be examined, two major mechanisms
have emerged: defects in the skin barrier and immune
dysregulation160,161. AD pathogenesis likely results from
an interplay of these two mechanisms, but immune dys-
function appears to play an outsized role in the develop-
ment of AD. Cutaneous barrier defects resulting from
filaggrin mutations are reviewed elsewhere162.
Non-lesional skin from patients with AD demon-
strates evidence of subclinical inflammation with a
pro-inflammatory cytokine milieu and increased num-
bers of TH2 cells, TH22 cells and, to a lesser degree,
TH17 cells163. However, immune signatures from the
lesional skin of adult and paediatric patients with AD

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suggest that there may be subtle differences in the dis-
ease process, which may be age related163. Children have
strong activation of TH2 cell-type and TH22 cell-type
cytokines; however, paediatric skin also has levels of
IL-9, IL-33 and TH17 cell-associated cytokines that are
higher than those in adults163. Filaggrin mutations can
predispose to the development of AD, and epidermal
barrier disruptions and skin inflammation are mutually
reinforcing processes, as perturbations of the epidermal
barrier intrinsically stimulate inflammation by activat-
ing keratinocytes to release disease-associated cytokines
and chemokines164,165. In humans with AD, peripheral
blood CCR8+CD4+ T cells are enriched for IL-5 expres-
sion, whereas CCR4+CD4+ T cells are enriched for IL-4
(ref. 166) . Furthermore, thymic stromal lymphopoie-
tin (TSLP) is expressed by epithelial cells, especially
keratinocytes, from patients with AD167. TSLP acti-
vates CD11c+ DCs and induces the production of TH2
cell-attracting chemokines. TSLP-activated DCs polarize
naive CD4+ T cells to produce IL-4, IL-5, IL-13 and TNF
while downregulating IL-10 and IFNγ167. TSLP appears
to have a dual role in that it directly communicates
with somatosensory nerves and induces TH2 cell-type
cytokines such as IL-13 and IL-31, which stimulate nerve
fibres directly and upregulate the release of cellular pru-
ritogens. The resulting neurogenic inflammation com-
pletes the vicious cycle by promoting TH2 cell responses,
keratinocyte proliferation and epidermal thickening168.
Recently available and highly successful AD treat-
ments highlight the critical importance of type 2 immune
responses to disease pathogenesis and the pathogenic
role of epidermal dysfunction in disease pathogenesis.
Dupilumab is a monoclonal antibody that targets the
IL-4Rα chain, which is shared by the receptors for IL-4
and IL-13 (Table 1). Clinical trials have demonstrated its
remarkable efficacy in the treatment of AD169. If psoriasis
can be described as a disease of the IL-17–IL-23 axis, AD
appears to be a disease of the IL-4–IL-13 axis. The degree
to which this is true for atopic diseases of other tissues
(such as asthma) remains to be elucidated. Therapeutic
targeting of the downstream results of epithelial damage
may provide additional insights into AD pathogenesis
and novel treatments. IL-33 is produced by a number of
cell types including keratinocytes and, along with TSLP,
is a potent stimulator of allergic type 2 inflammation170.
This makes IL-33 a particularly attractive target in AD
and, indeed, this is an area of active investigation. IL-22
also plays an important role in maintaining the epithe-
lial barrier171, and clinical trials using an antibody to
target IL-22 in AD have shown promise172, suggesting
that IL-22 plays a pathogenic role in AD. Indeed, novel
treatments that target type 2 immune responses and bar-
rier dysfunction may improve the array of therapeutic
options for patients with AD.
T cells in alopecia areata. Alopecia areata is a cutane-
ous disorder that results in non-scarring hair loss with
a cumulative lifetime incidence of 2%173. The diagno-
sis of alopecia areata is made clinically, and the disease
typically manifests with sharply demarcated, annular
patches of hair loss without atrophy. Less commonly, loss
of all scalp hair (alopecia totalis) or all terminal hair on
Nature Reviews | Immunology
Reviews
the body (alopecia universalis) can occur174. The exact
pathogenesis of alopecia areata is an area of active inves-
tigation, but evidence suggests that genetic and environ-
mental factors cause an autoimmune reaction to the hair
follicles175. A genome-wide association study implicated
HLA-DR and several genes involved in the regulation of
Treg cells and cytotoxic T cells in disease susceptibility176.
A recent meta-analysis confirmed that HLA-DR is the
largest risk factor for alopecia areata. These MHC class II
genes are highly linked to the functions of CD4+ T cells,
which are important effector cells in alopecia areata177.
Experimental evidence also points to the importance
of CD8+ T cells in mediating the alopecia areata disease
process. The hair follicle is an immune-privileged site,
with low levels of MHC expression178. A proposed model
of alopecia areata pathogenesis suggests that a break in
immune privilege results in a subsequent assault on the
hair follicle at the level of the bulb by oligoclonal and
autoreactive CD8+ T cells178. The peribulbar lymphocytic
infiltrate induces hair follicle keratinocytes to undergo
apoptosis that results in inhibition of cell division within
the hair matrix and of hair shaft production179. In one
study in which scalp explants from patients with alo-
pecia areata were transplanted into severe combined
immunodeficient (SCID) mice and injected with autolo-
gous T cells isolated from involved scalp, T cells that had
been cultured in the presence (but not the absence) of
hair follicle homogenate induced changes reminiscent
of alopecia areata, including hair loss and perifollicular
infiltrates of T cells, along with HLA-DR and ICAM1
expression of the follicular epithelium180. Furthermore,
cytotoxic CD8+NKG2D+ T cells are both necessary and
sufficient for the induction of alopecia areata in a mouse
model of disease181. Transcriptional profiling of mouse
and human alopecia areata skin revealed gene expres-
sion signatures indicative of cytotoxic T cell infiltration,
an IFNγ response and upregulation of several γ-chain
cytokines known to promote the activation and survival
of IFNγ-producing CD8+NKG2D+ effector T cells181.
Therapeutic targeting of Janus-activated kinases (JAKs,
which are key signalling molecules downstream of the
IFNγ receptor) has established the central role of IFNγ
in alopecia areata disease pathogenesis. Several reports
have demonstrated hair regrowth in patients with alope-
cia areata and in mouse models upon treatment with JAK
inhibitors181,182 (Table 1). Multiple clinical trials involving
systemic and topical JAK inhibitors are underway183.
T cells in vitiligo. Vitiligo is a cutaneous autoimmune
disorder that results in white, depigmented patches of
skin owing to the destruction of melanocytes by the
immune system184. A better understanding of vitiligo
disease pathogenesis has led to new treatment strate-
gies. Both immune dysfunction and intrinsic melano-
cyte abnormalities are proposed mechanisms of disease
initiation185. Accordingly, CD8+ T cells are both neces-
sary and sufficient to mediate melanocyte destruction
in human subjects and have been a focus of active inves-
tigation186. Similarly, melanocytes from patients with
vitiligo grow poorly ex vivo and are more susceptible
to oxidative stress187. The role of oxidative stress in the
pathogenesis of vitiligo is reviewed elsewhere188.
Reviews

Recent evidence has identified CD8+ T cells as key
drivers of vitiligo disease progression186. Gene expression
analysis of human lesional skin revealed upregulation of
IFNγ and IFNγ-dependent genes, including those encod-
ing CXCR3 and its ligands, CXCL9, CXCL10 and CXCL11
(ref.189). These findings were consistent with functional
studies in mouse models of vitiligo190. Disruption of the
IFNγ–chemokine signalling axis prevents T cell recruit-
ment to the skin, subsequent melanocyte destruction
and pigment loss. Furthermore, blockade of this signal-
ling axis not only prevented vitiligo disease in mice but
also reversed established disease190,191. These findings led
to therapeutic targeting of the IFNγ signalling pathway
clinically with JAK inhibitors. Patients with vitiligo that
received either of the JAK inhibitors tofacitinib or ruxol-
itinib rapidly repigmented their skin. A patient treated
with ruxolitinib was found to have an increased serum
level of CXCL10, which rapidly decreased after treatment
with the JAK inhibitor192–194 (Table 1). This observation
was consistent with the hypothesis that the mechanism of
improvement was through inhibition of IFNγ signalling
and resulting loss of chemokine production.
Vitiligo lesions frequently recur at previous sites
upon treatment cessation, suggesting a potential role for
TRM cells. A recent report demonstrated that TRM cells
are highly enriched in the skin of patients with vitiligo
and show cytotoxic effector functions when exposed to
inflammatory cytokines195. Furthermore, another group
found that TRM cells are present in vitiligo lesions in a
mouse model of melanoma and vitiligo and might be
responsible in part for mediating protection against
recurrence of melanoma 196. Antibody blockade of
CD122 (a component of the IL-15R) in a mouse model
of vitiligo results in the depletion of pathogenic TRM cells
in lesional skin and reversal of disease69. Future stud-
ies might determine that targeting TRM cells in patients
with vitiligo could be an effective treatment strategy and
could be durable, even after discontinuing treatment.
Conclusions and future directions
Ultimately, the study of cutaneous T cells has as its
goal the improvement of human health. Our new
knowledge of the basic immunobiology of skin has
very recently permitted an explosion of novel ther-
apies for T cell-mediated skin disorders. A derma-
tologist treating moderate to severe psoriasis may
choose between highly targeted biologics directed
at TNF, IL-17 or IL-23, options that were unthink-
able in the 20th century. Therapeutic antibodies to
the receptor for IL-4 and IL-13 have revolutionized the
treatment of AD and demonstrated that T cells are
central to this disorder. As the immunopathological
beginnings of alopecia areata and vitiligo are mech-
anistically dissected, JAK inhibitors targeting T H1
cell cytokines have emerged as promising therapies197
(Table 1) . There are a host of other T cell-mediated
skin disorders, which, when studied mechanistically,
may result in the development of new therapies or a
novel use for an existing drug. Many other therapeu-
tic antibodies directed against cytokines and chemo­
kines are either being developed or already in clinical
trials143,198,199. Furthermore, as discussed above, TRM cells
have been demonstrated as fundamentally important
in normal and diseased skin2,3 and are the likely targets
of these drugs. Looking backwards, dermatologists
have successfully treated T cell-mediated skin disor-
ders with skin-directed therapies (including topical
medicines and ultraviolet light) for more than 100
years, unaware that their target was the then undis-
covered pathogenic skin TRM cells. The next frontier
may involve dislodging pathogenic TRM cells rather
than simply episodically suppressing their function,
as all current therapies do. If pathogenic TRM cells can
be dislodged while preserving at least some protective
TRM cell function, durable remissions may be possi-
ble2,3,200. Finally, it is important to emphasize that the
scientific study of immune-mediated skin diseases can
be more readily accomplished than that of any other
human organ, largely owing to its accessibility. While
immune-mediated diseases of other organs will have
unique features, there is a great deal of common mech-
anism, and it is inevitable that the study of skin immu-
nology and immunopathology will inform all human
immune-mediated disorders.
Published online xx xx xxxx

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Acknowledgements
A.W.H. is supported by a Career Development Award from
the Dermatology Foundation. T.S.K. is supported by grants
R01 AR065807, R01 AI127654 and R01 CA210372 from
the US National Institutes of Health.
Author contributions
Both authors contributed to researching data, discussion of
content and to the writing, review and editing of this article.
Competing interests
The authors declare no competing interests.
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Reviewer information
Nature Reviews Immunology thanks P. Scott and the other
anonymous reviewer(s) for their contribution to the peer
review of this work.