kabashima2018

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The skin is a barrier organ that separates the body 
from the outside environment. Because many physical, 
chemical and microbial insults affect the skin, various 
types of immune cells reside in or are recruited into the 
skin to maintain skin homeostasis upon inflammatory 
challenges.
In the epidermis, Langerhans cells (LCs), which are 
a unique subset of professional antigen-presenting cells 
(APCs), reside between keratinocytes (Fig. 1a). Although 
LCs were previously considered a subset of dendritic cells 
(DCs) because they migrate to the lymph nodes, recent 
ontogenic studies have revealed that LCs are actua-
lly a subset of tissue-resident macrophages that acquire 
a DC-like phenotype and functions upon further differ-
entiation in the skin1,2. In addition to LCs, two specific 
subsets of T cells can be found in the mouse epidermis: γδ 
T cells and CD8+ resident memory T (TRM) cells. γδ T cells 
are a subset of innate immune cells that reside perma-
nently in the epidermis of mice but not humans. CD8+ TRM  
cells comprise populations of non-circulating memory 
T cells that appear after the resolution of skin inflam-
mation, such as that caused by herpes simplex virus 
(HSV) infection3. TRM cells have been identified in var-
ious non-lymphoid tissues4,5, and their longevity differs 
between tissues. For example, skin TRM cells in mice per-
sist for over a year6, whereas lung TRM cells are maintained 
for only a few months7.
Anatomically, the most unique feature of the epider-
mis is the existence of the stratum corneum8,9 (Box 1; 
Fig. 1a). The stratum corneum is the outermost layer 
of the epidermis and consists of piles of dead keratino-
cytes (known as corneocytes) and intercellular lipids. 
This structure blocks the entry or exit of water and 
water-soluble substances; thus, it is essential for animals 
to survive outside of water. Its barrier function is, how-
ever, imperfect because it contains many holes for skin 
appendages, such as hair follicles and sweat ducts. Skin 
appendages are useful to protect the body from mechan-
ical damage, ultraviolet light, temperature changes and 
dryness. Thus, animals develop skin appendages at 
the expense of the integral stratum corneum. It is of 
note that numerous microorganisms (known as the 
microbiota) live on the surfaces of our body in a com-
mensal relationship and may influence our cutaneous 
immune reactions10,11. As skin appendages lack the 
stratum corneum, the skin microbiota coexists beside 
living keratinocytes in these areas11. This results in skin 
appendages being immunologically unique spots.
In the dermis, there are several types of innate 
immune cells, including dermal DCs, macrophages, 
mast cells, γδ T cells and innate lymphoid cells (ILCs)12. 
In the steady state, small numbers of neutrophils, mono-
cytes and αβ T cells survey the dermis for pathogens; in 
response to inflammatory stimuli, many more immune 
cells rapidly accumulate in the dermis13–15. Anatomically, 
the dermis is characterized by an abundant extracellu-
lar matrix (ECM), comprising collagen and elastin fibres 
that fill the extracellular spaces. The ECM provides a 
scaffold for immune cell migration16. Throughout the 
ECM, mesh-like networks of blood and lymph vascu-
latures and neurons are distributed. Immune cells are 
constantly recruited to the skin via the blood vascular 
systems. The recruited cells include the precursor cells of 
skin-resident DCs and macrophages as well as some pas-
senger cells, such as neutrophils and T cells, which scout 
for foreign pathogens. Dermal DCs that have captured 
The immunological anatomy 
of the skin
Kenji Kabashima 1,2*, Tetsuya Honda1, Florent Ginhoux 2,3 and Gyohei Egawa1*
Abstract | The skin is the outermost organ of the body and is continuously exposed to external 
pathogens. Upon inflammation, various immune cells pass through, reside in or are recruited to the 
skin to orchestrate diverse cutaneous immune responses. To achieve this, immune cells interact 
with each other and even communicate with non-immune cells, including peripheral nerves 
and the microbiota. Immunologically important anatomical sites, such as skin appendages 
(for example, hair follicles and sweat glands) or postcapillary venules, act as special portal sites for 
immune cells and for establishing tertiary lymphoid structures, including inducible skin-associated 
lymphoid tissue. Here, we provide an overview of the key findings and concepts of cutaneous 
immunity in association with skin anatomy and discuss how cutaneous immune cells fine-tune 
physiological responses in the skin.
1Department of Dermatology, 
Graduate School of Medicine, 
Kyoto University, Kyoto, 
Japan.
2Singapore Immunology 
Network (SIgN) and Institute 
of Medical Biology (IMB), 
Agency for Science, 
Technology and Research 
(A*STAR), Biopolis, 
Singapore.
3Shanghai Institute of 
Immunology, Shanghai 
JiaoTong University School of 
Medicine, Shanghai, China.
*e-mail: kaba@ 
kuhp.kyoto-u.ac.jp; gyohei@
kuhp.kyoto-u.ac.jp
https://doi.org/10.1038/ 
s41577-018-0084-5
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http://orcid.org/0000-0002-0773-0554
http://orcid.org/0000-0002-2857-7755
mailto:kaba@
kuhp.kyoto-u.ac.jp
mailto:kaba@
kuhp.kyoto-u.ac.jp
mailto:gyohei@kuhp.kyoto-u.ac.jp
mailto:gyohei@kuhp.kyoto-u.ac.jp
https://doi.org/10.1038/s41577-018-0084-5
https://doi.org/10.1038/s41577-018-0084-5
FAS ligand
Specific ECM 
components
Treg cell and/or
CD4+ TRM cell
Infundibulum
Isthmus
IL-17A
Neutrophil
T
H
17 cells
T
H
17 cells
IL-17A
Bulge
Demodex sp.
(mite)
Monocyte
and/or
macrophage
CD8+ 
T
RM
 cell
CCL20
and/or 
IL-15
CCL8
IL-10
TGFβ
IL-1β
TGFβ IL-6
CCL2
and/or
IL-17
Microbiota
Lymph duct
DC
P. acnes
T
RM
 cell LC
Sweat duct
Stratum
corneum
Epidermis
Hair shaft
a
b c
Stratum 
corneum
Stratum 
granulosum
Stratum 
spinosum
Stratum 
basale
Lymph 
duct
Subcutaneous
adipose tissue
Dermis
Blood 
vessel
γδ T cell
Keratinocyte
Tight
junction
Sebaceous
gland
Sweat
gland
Fig. 1 | Physical and immunological barrier of the skin. a | Structures of the skin. In the epidermis, tight junctions are 
formed underneath the stratum corneum (in the stratum granulosum), and three types of immune cell populations 
(Langerhans cells (LCs), γδ T cells and resident memory T (TRM) cells) reside between keratinocytes. b | A schematic of 
immune privilege of hair follicles. Hair follicles express FAS ligand while lacking MHC class II expression, and they are 
surrounded by immune-suppressive extracellular matrix (ECM) components. TRM cells and regulatory T (Treg) cells are found 
in the vicinity of hair follicles. Numerous microorganisms live deep inside the hair follicles. Follicular keratinocytes in 
different parts of the follicle produce distinct chemokines and control the traffic of leukocytes in the skin. c | A schematic 
of immune modulation by sebaceous glands. The bacterium Propionibacterium acnes stimulates sebaceous glands to 
produce IL-1β, IL-6 and transforming growth factor-β (TGFβ), which leads to the activation of dermal dendritic cells (DCs) 
that can preferentially prime T helper 17 (TH17) cells. The TH17 cells promote neutrophil recruitment and inflammation at 
the hair follicle. CCL , CC-chemokine ligand.
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cutaneous antigens migrate back to the draining lymph 
nodes via the lymphatics17. Neurons endow a sensory 
function to the skin and can directly communicate with 
immune cells18,19.
Recent developments in imaging studies in vivo have 
demonstrated the dynamic behaviour of immune cells in 
the skin and underscored the unique distribution pattern 
of each immune subset that is related to skin anatomical 
structures. Thus, knowledge of the interaction between 
immune cells and non-immune structures is important 
for a deep understanding of the basic mechanisms of 
cutaneous immune reactions. In this Review, we dis-cuss the unique nature of some anatomical parts and 
non-immune components of the skin (for example, hair 
follicles, blood vessels, neurons, sebaceous glands and 
the microbiota) and focus on the function of a specific 
immunological unit, called inducible skin-associated 
lymphoid tissue (iSALT)20, which has an essential role 
in the induction of cutaneous adaptive immunity.
Immunological anatomy of the epidermis
The main function of keratinocytes is to maintain the 
physical barrier of the skin by developing into the stra-
tum corneum. This is achieved by keratinocytes passing 
through three inner cell layers: the stratum basale, the 
stratum spinosum and the stratum granulosum (Fig. 1). 
Keratinocytes are not merely a progenitor of the bar-
rier but also a component of the innate immune sys-
tem. They express several different pattern recognition 
receptors and produce a variety of cytokines, including 
thymic stromal lymphopoietin (TSLP), tumour necro-
sis factor (TNF), IL-33 and other IL-1 family members, 
upon inflammation21. These cytokines are essential for 
activation of skin-resident immune cells and for immune 
cell recruitment to the skin (reviewed previously22). As 
skin appendages lack the stratum corneum, they are 
points of entry for external pathogens. In addition to 
low-molecular-weight compounds, such as haptens, 
living microorganisms (for example, bacteria, fungi, 
viruses, parasites and mites such as Demodex spp.) 
can easily reach the vicinity of keratinocytes living in 
these areas11 (Fig. 1b). To handle this unique situation, 
hair follicles are equipped with specific immunological 
properties, as described below.
Monocyte interaction with hair follicles. Previous 
in vivo imaging studies demonstrated that hair folli-
cles interact closely with recruited monocytes23. When 
LCs were depleted by diphtheria toxin treatment of 
Langerin-DTR mice, GR1high monocyte-derived LC pre-
cursor cells appeared around hair follicles within 
weeks23. This suggested that hair follicles are portal 
sites where LC precursors enter the epidermis. Such 
LC repopulation is dependent on CC-chemokine 
receptor 2 (CCR2) and CCR6, suggesting that hair fol-
licles constitutively produce chemoattractants for LCs. 
Fluorescence-activated cell sorting-based cell isolation 
and gene expression analyses revealed that the chemo-
kine expression patterns of follicular keratinocytes differ 
according to their location. Specifically, keratinocytes in 
the hair follicle infundibulum produce CC-chemokine 
ligand 20 (CCL20); keratinocytes in the isthmus produce 
CCL2; and keratinocytes around the hair bulge region 
produce CCL8 (Fig. 1b).
Monocyte-derived cells also rally around hair fol-
licles during inflammation. These cells have several 
confusing synonyms and have been referred to as 
inflammatory monocytes, inflammatory macrophages 
and inflammatory DCs. When entering the epider-
mis, they are called inflammatory dendritic epidermal 
cells24. After the induction of skin inflammation by hap-
ten painting, CX3C-chemokine receptor 1 (CX3CR1)+ 
monocyte-derived cells form clusters around hair fol-
licles within a day in a CCR2-dependent manner25.
Although the immunological function of these clus-
ters remains unclear, the activation of T cells and their 
production of IFNγ is facilitated by cluster formation, 
suggesting that antigen presentation in the skin under 
inflammatory conditions depends, at least in part, on 
activated inflammatory monocytes.
T cell interaction with hair follicles. In contrast to the 
folliculotropic properties of monocytes, hair follicles 
have a repellent nature towards effector T cells in the 
steady state, which has led the hair follicle to be classified 
as a site of immune privilege26 (Fig. 1b). This is charac-
terized by the downregulation of MHC class I expres-
sion in follicular keratinocytes, the local production 
of potent immunosuppressants (such as transforming 
growth factor-β1 (TGFβ1) and IL-10), the establish-
ment of a unique ECM surrounding the hair follicle 
and the production of FAS ligands to delete autoreac-
tive FAS-expressing T cells. Why hair follicles have this 
immune privilege is still under discussion, but it likely 
leads to the sequestration of not only self-antigens in 
hair follicles but also colonized microorganisms, pre-
venting their exposure to T cells. As such, the collapse of 
immune privilege at these sites and the development 
of T cell responses against the skin microbiota may 
potentially result in autoimmune responses against hair 
follicles, such as those observed in alopecia areata27.
By contrast to their repellent effect on effector T cells, 
hair follicles harbour skin-resident TRM cells, which are 
responsible for long-term skin immunity28. CD4+ and 
CD8+ TRM cells predominantly reside around hair fol-
licles. Keratinocytes in the infundibulum and isthmus 
produce IL-15, which is required for the persistence of 
Langerin-DTR mice
Mice that express diphtheria 
toxin receptor (DTR) under the 
control of the Langerin gene 
promoter. Treatment of these 
mice with diphtheria toxin 
leads to the deletion of all 
Langerin-expressing cells.
Alopecia areata
A patchy hair loss mainly 
occurring in the scalp. it is 
believed to be one of the 
autoimmune diseases.
Box 1 | Stratum corneum
The stratum corneum is the outermost layer of the 
epidermis, and it has a central role in maintaining the 
barrier function of the skin. Its thickness ranges from 10 
to 30 μm and varies substantially between body sites. 
In the stratum corneum, keratinocytes become flattened 
and denucleated and are called corneocytes; their 
membranes are replaced by a unique barrier structure 
known as the cornified envelope8,88. Intercellular spaces 
are filled with lipids. These structures are often described 
as the ‘bricks’ (corneocytes) and ‘mortar’ (intercellular 
lipids), which together provide a highly hydrophobic 
barrier against the environment. Importantly, the stratum 
corneum is not formed at skin appendages, which thus 
provides an outside-to-inside route for small-molecule 
drugs and chemicals and an inside-to-outside route for 
transepidermal water loss.
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CD8+ TRM cells in the epidermis. By contrast, IL-7, which 
is required for both CD4+ and CD8+ TRM cells, is pre-
dominantly produced by infundibulum keratinocytes. 
Another study has shown that CD11b+ cells (most likely 
macrophages and/or DCs) and CD8+ T cells around the 
hair follicles produce CCL5, which is proposed to recruit 
memory CD4+ T cells to form clusters29. During second-
ary immune responses, most IFNγ-producing T cells 
localize around the hair follicles, suggesting that these 
clusters may protect against pathogens by efficiently acti-
vating effector T cells. Because hair follicles facilitate the 
trafficking of DCs23 as well as T cells28, they may serve 
as an essential site for antigen presentation in the skin 
under certain conditions.
As for CD4+ regulatory T (Treg) cells, they are pre-
dominantly distributed near the hair bulge area where 
hair follicular stem cells reside. Intriguingly, the deple-
tion of skin-resident Treg cells results in the perturbation 
of hair cycles30. These findings suggest that Treg cells 
can control hair cycles by interacting with hair follicu-
lar stem cells and that they are essential for preserving 
immune privilege in the follicles.
Immune modulation by sebaceous glands. Sebaceous 
glands are another unique structure that accompanies 
hair follicles (Fig. 1c). These glands secrete lipids as part of 
the skin barrier function and produce antimicrobial pep-
tides and cytokines and chemokines that modulate skin 
immunity. In pathological conditions, such as acne, IL-17-
producing T helper 17 (TH17) cells accumulate around 
sebaceous glands31. In vitro analysis demonstrated that 
Propionibacterium acnes induced sebocytes to produce 
IL-6, TGFβ and IL-1β, which activateddermal DCs to 
preferentially prime TH17 cells31. In another pathologi-
cal context — eosinophilic pustular folliculitis — sebaceous 
glands were surrounded by a massive number of eosin-
ophils32. In this condition, prostaglandin D2 (PGD2) 
expression is upregulated in hair follicles, which acts on 
sebocytes to produce the eosinophil chemoattractant 
CCL26. It is evident that there are many potential ways in 
which sebocytes can modulate skin immune responses.
Influence of the skin microbiota. Numerous microor-
ganisms cover skin surfaces and reside in skin append-
ages (Fig. 1b,c). These microorganisms have a profound 
effect on immune processes of the skin11. The metabo-
lites and/or structural components of microorganisms 
may influence both innate and adaptive immunity. For 
example, Staphylococcus epidermidis, which constitutes 
a major population of commensal bacteria found on the 
skin, produces lipoteichoic acid that acts selectively on 
keratinocytes through Toll-like receptor 3 (TLR3) to 
inhibit inflammatory cytokine release33. S. epidermidis 
is also directly captured by dermal APCs, probably at 
skin appendages, and antigens from the bacteria are pre-
sented on MHC class I molecules by APCs in the drain-
ing lymph nodes34. As a result, S. epidermidis-specific 
CD8+ T cells that express IL-17A or IFNγ (and have been 
referred to as Tc17 or Tc1 cells, respectively) are recruited 
to the skin in the absence of overt inflammation34. It is 
of note that S. epidermidis-specific CD8+ T cells have a 
unique gene expression profile in that they express genes 
associated with immunoregulation, angiogenesis, tissue 
remodelling and ECM production. Consistent with 
this, S. epidermidis-specific CD8+ T cells promote rapid 
keratinocyte proliferation and accelerate wound healing.
As corneocytes are dead cells and express no active 
biological sensors for microorganisms, microorgan-
isms in the skin appendages are likely to have a greater 
influence on cutaneous immunity than microorganisms 
residing on the stratum corneum. Indeed, the compo-
sition of the microbiota varies substantially between 
the surface areas and the deeper areas of the skin35. For the 
same reason, pathogenic microorganisms target skin 
appendages unless barrier-disrupted injury exists. Thus, 
it should be emphasized that the method used to sample 
skin microbiota, such as swab, tape stripping and skin 
biopsy, is important to consider when interpreting data 
from skin microbiota studies35.
The expansion of pathogenic bacteria and fungi 
in skin appendages easily stimulates neighbouring 
keratinocytes to produce inflammatory cytokines and 
chemokines that can recruit neutrophils and monocytes, 
leading to the development of folliculitis and hidrade-
nitis. By contrast, pathogenic viruses that invade skin 
appendages sometimes establish latent infection and 
form their ‘nest’ in these sites (for example, human pap-
illoma viruses), probably owing to the repellent nature 
of these appendages against T cells36. How the cutaneous 
immune system discriminates pathogenic microorgan-
isms from commensal microorganisms has yet to be 
fully elucidated, and characterizing the critical molecules 
required for this recognition would be of clinical interest.
Immune responses in the dermis
Immune modulation by dermal blood vessels. Dermal 
blood vessels can be divided into four different parts 
with distinct functions: arteries, capillaries, postcapil-
lary venules and collecting venules (Fig. 2). Among these 
vessels, postcapillary venules have a unique property that 
is particularly important during inflammation. Adjacent 
blood endothelial cells are sealed with tight junctions 
and adherence junctions. These barrier structures limit 
the passage of plasma proteins larger than 70 kDa, sug-
gesting that extravasation of albumin and immunoglob-
ulins (which have molecular masses of approximately 
70 kDa and 150 kDa, respectively) is limited under 
homeostatic conditions37 (Fig. 2). Importantly, this vascu-
lar permeability is variable only at postcapillary venules. 
During inflammation, intercellular tight and/or adher-
ence junctions are diminished, and immunoglobulins, 
albumin and water shift into the dermal interstitium and 
lead to tissue swelling. This phenomenon demonstrates 
that postcapillary venules are specific portal sites that 
allow key mediators of humoral immunity to access the 
skin under inflammatory conditions (Fig. 2).
In postcapillary venules, endothelial cells are sur-
rounded by the basement membrane and pericytes, 
and macrophages and mast cells are located nearby. 
Recent studies using a mouse model of Staphylococcus 
aureus infection have demonstrated that these cellular 
and matrix components act as integrated functional 
units, termed the ‘perivascular extravasation units’38 
(Fig. 2). In these units, perivascular macrophages are 
Eosinophilic pustular 
folliculitis
A recurrent folliculitis that is 
often formed in the face. in this 
condition, many eosinophils 
are pathologically accumulated 
around hair follicles.
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critically important for neutrophil extravasation. 
Perivascular macrophages express high levels of the 
neutrophil-attracting chemokines CXC-chemokine 
ligand 1 (CXCL1) and CXCL2, and neutrophils extra-
vasate in the vicinity of perivascular macrophages. These 
macrophages are depleted when they are exposed to the 
S. aureus-derived exotoxin α-haemolysin, and in 
the absence of perivascular macrophages, neutrophil 
recruitment to the skin is markedly suppressed38.
Postcapillary venules also play a crucial role dur-
ing T cell recruitment to and activation in the skin20 
(Fig. 2). During cutaneous inflammation, T cells, DCs 
and perivascular macrophages form clusters, which have 
been termed iSALT, around postcapillary venules. The 
iSALT provides a site of antigen presentation in the skin, 
which is critical for the elicitation of adaptive immunity. 
The induction and function of iSALT will be discussed 
in detail in a later section.
Neuro-immune interactions in the skin. The skin func-
tions as both a barrier and a sensory interface. It is inner-
vated by abundant sensory nerves and also by a smaller 
number of autonomic nerve fibres. Neurons form 
mesh-like bundles in the dermis, and a large number of 
the nerve ends reach the epidermis (Fig. 3a). Whole-mount 
immune staining analysis revealed that a large fraction of 
dermal DCs are in close contact with neurons, suggest-
ing there is neural regulation of DC functions19. Until 
recently, it was unclear whether peripheral neurons reg-
ulate cutaneous immune responses. However, studies 
involving the genetic and pharmacological ablation of 
transient receptor potential subfamily V member 1 (TRPV1)-
expressing sensory neurons have demonstrated that 
neurons have key roles in regulating cutaneous immune 
responses19,39.
For example, skin inflammation induced by the TLR7 
ligand imiquimod is significantly suppressed with the 
pharmacological ablation of TRPV1+ sensory nerves19. 
Topical application of imiquimod causes a skin inflam-
mation that is similar to human psoriasis, particularly in 
terms of the dependence of the response on the IL-17–
IL-23 axis40. Following nerve deletion, dermal DCs fail 
to produce IL-23 in imiquimod-exposed skin and, con-
sequently, the local production of IL-17 by dermal γδ 
T cells is significantly suppressed40. In a Candida albicans 
infection model, TRPV1+ sensory nociceptors directly 
sense fungal agents and release calcitonin gene-related 
peptide (CGRP); this peptide upregulates the production 
of IL-23 by CD301b+ DCs, which in turn drives IL-17A 
production by dermal γδ T cells18 (Fig. 3a).
In contrast to these pro-inflammatory roles for cuta-
neous neurons, immunoregulatory roles for neurons 
have been reported in the squaric acid dibutylester 
(SADBE)-induced model of contact hypersensitivity 
(CHS)41 (Box 2). Upon SADBEapplication to the skin, 
TRPV1-expressing neurons directly recognize this hapten 
and suppress the pro-inflammatory function of dermal 
macrophages. By contrast, when TRPV1-deficient mice 
are treated with SADBE, dermal macrophages abundantly 
produce pro-inflammatory cytokines, such as TNF, IL-1β 
and IL-6, and this markedly exacerbates skin inflamma-
tion (Fig. 3a). These findings suggest that neurons are 
important immune regulators that can either promote or 
suppress skin inflammation depending on the context.
Immunity in subcutaneous adipose tissue
Below the dermis, subcutaneous adipose tissue is distrib-
uted throughout the body. It acts as padding, an energy 
reserve and insulation for thermoregulation42. Adipose 
tissue contains a variety of immune cells, including 
T cells, B cells and macrophages. In the obese condi-
tion, however, the number of macrophages is increased 
by fourfold compared with the lean condition43, and 
the production of a variety of inflammatory media-
tors, termed adipokines, is increased. These mediators 
include adiponectin, leptin, IL-6 and TNF. Subcutaneous 
adipose tissue is also essential for host defence against 
Immunoglobulin Low-molecular-weight
proteins (70 kDa)
Stable state
b
Inflammatory state
Water
Water
Arteriole Capillaries
Postcapillary
venules
Collecting
venules
a
T cell
DC
Immunoglobulins
Perivascular 
macrophage
Neutrophils
A unit for
neutrophil
extravasation
Hyper-permeability
for humoral immunity
iSALT for T cell
activation
Fig. 2 | A specific contribution of postcapillary venules in cutaneous immunity. a | 
Skin blood vessels can be divided into four distinct types: arterioles, capillaries, 
postcapillary venules and collecting venules. Among them, postcapillary venules display 
unique properties during inflammation. Inducible skin-associated lymphoid tissues 
(iSALT) are induced for the activation of T cells that have infiltrated the skin. Perivascular 
extravasation units are essential for neutrophil recruitment. Perivascular macrophages 
are critically important for neutrophil extravasation. Hyper-permeabilization occurs in 
postcapillary venules, and this enables the recruitment of immunoglobulins from the 
blood. b | A schematic of hyper-permeabilization of postcapillary venules is shown. 
In the steady state, only plasma components with a molecular mass of 70 kDa), such as 
albumin and immunoglobulins, freely pass through the hyper-permeabilized blood vessel 
walls. DC, dendritic cell.
Transient receptor potential 
subfamily V member 1
(TRPV1). Also known as 
capsaicin receptor; TRPV1 is a 
cation channel member 
selectively expressed on 
peripheral sensory neurons 
that serves as a molecular 
sensor (nociceptor) for noxious 
stimuli.
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S. aureus infection via the production of cathelicidin, 
which kills bacteria44. This suggests diverse roles for 
adipocytes in cutaneous immunity.
Recent in vivo imaging analysis revealed that adi-
pocytes form clusters around dermal blood vessels, 
which are termed perivascular adipose tissues (PATs)45 
(Fig. 3b). The functions of PATs in the skin remain unre-
solved, but they may be involved in vascular regula-
tion or could provide a harbour for specific subsets of 
immune cells, analogous to the role played by PATs in 
other organs46,47.
Skin anatomy and induction of adaptive immunity
Before eliciting adaptive immune responses in the 
skin, external antigens breach the skin barrier and are 
captured by cutaneous DCs. Anatomically, the barrier 
function of the skin is dependent on two key structures, 
the stratum corneum and the tight junction8,9 (Fig. 1). 
As described above, skin appendages lack the stratum 
corneum, and the tight junction is thus the primary bar-
rier in these tissues. As skin appendages act as ‘shunt 
routes’ into the body for drugs and chemicals, the 
tight junction is considered the determinant of skin 
barrier functions.
Most contact dermatitis is caused by haptens. 
Haptens are small molecules that acquire antigenicity 
only when binding to self-proteins in the skin (lead-
ing to the formation of hapten–self complexes). The 
tight junction limits the passage of molecules larger 
than 500 Da, and the molecular weight of haptens is 
less than this. As such, haptens can easily pass through 
the tight junction and penetrate the skin under phys-
iological conditions (Fig. 4). By contrast, macromole-
cules, such as proteins, are too large to penetrate tight 
junctions and cannot diffuse into the underlying skin 
tissues. However, during inflammation, activated 
LCs elongate their dendrites outward beyond the 
tight junction and uptake external antigens48. This is 
another shunt route into the skin, mediated by LCs, 
that plays a crucial role in percutaneous sensitization 
by macromolecular proteins.
Antigen presentation by cutaneous APCs. The antigens 
that breach the stratum corneum and tight junctions are 
then captured by the second line of the immunologi-
cal barrier, cutaneous DCs. DCs are a diverse family of 
cells that play a crucial role in linking our innate and 
Dermal 
DC
Neuron Dermal γδ T cells Blood 
vessel
Perivascular
adipose tissue
LC
Tight
junction
a b
Macrophages
HaptensFungi and/or bacteria
IL-17ACGRP
IL-23
Stratum
corneum
Stratum
granulosum
Stratum
spinosum
Stratum
basale
Fig. 3 | Neuro-immune interactions and perivascular adipose tissue in the skin. a | A schematic of neuro-immune 
interactions in the skin. Components of fungi and bacteria as well as haptens can be directly sensed by transient receptor 
potential subfamily V member 1 (TRPV1)+ nociceptors. The activated TRPV1+ nerves produce calcitonin gene-related 
peptide (CGRP) to upregulate the production of IL-23 by CD301b+ dendritic cells (DCs), which in turn drives IL-17A 
production by dermal γδ T cells. TRPV1+ nerves also recognize haptens and modulate skin inflammation by regulating the 
function of dermal macrophages. b | Perivascular adipose tissue in the skin. BODIPY (green) and fluorescent-conjugated 
dextran (red) were simultaneously injected to visualize lipophilic cells and blood vessels, respectively. Second-harmonic 
generation represents dermal collagen fibres (blue). LC, Langerhans cell.
Box 2 | Contact hypersensitivity responses
The contact hypersensitivity (CHS) response provides a murine model of allergic contact 
dermatitis. It is induced by small compounds called haptens. Haptens are conjugated to 
self-proteins and are captured by cutaneous dendritic cells (DCs). DCs carry the hapten–
self complex to the draining lymph nodes and mediate antigen presentation to prime 
antigen-specific effector T cells, namely, cytotoxic CD8+ T cells and T helper 1 cells (known 
as the sensitization phase)73,89,90. With subsequent exposure to the same haptens, activation 
of the effector T cells is induced by antigen-presenting cells in the skin, leading to 
spongiotic dermatitis (known as the elicitation phase)68.
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adaptive immune system49. Generally, four cell types 
were classified in the DC family in the skin: epidermal 
LCs, conventional DCs (cDCs), plasmacytoid DCs and 
monocyte-derived DCs. cDCs can be further subdi-
vided into the cDC1 and cDC2 subsets on the basis of 
subset-specific gene expression profiles, their depend-
ence on different transcription factors and unique subset 
functions50,51.
During inflammation and neoplasm formation in the 
skin (Box 3), effector T cells are recruited and retained 
in the skin with limited antigen dependency52. The 
skin-infiltrating effector T cells actively migrate in order 
to explore antigens presented by cutaneous APCs53. 
Once they encounter their cognate antigens, effector 
T cells initiate stable contact with APCs and are activatedto produce inflammatory cytokines52,54,55. The motility 
and the activation status of effector T cells are inversely 
correlated and finely regulated52.
In the elicitation of CHS, dermal DCs are the most 
important APCs in the skin and form clusters for effi-
cient antigen presentation to T cells20 (Fig. 5). In addition 
to dermal DCs, several other cell populations, such as 
mast cells and LCs, are proposed as possible APCs in 
the skin. Mast cells participate in antigen presentation 
in the skin in CHS by acquiring MHC class II molecules 
from DCs56. Basophils may also act as APCs in the skin 
because they can also acquire MHC class II molecules by 
trogocytosis and present antigens to induce TH2 cells in 
the lymph nodes57. Although the role of LCs as APCs 
in the elicitation of CHS remains unclear, LCs may have 
potential APC functions in a graft versus host disease 
model, where the depletion of LCs in the effector phase 
causes impaired CD8+ T cell activation in the skin58. 
In addition, a recent report using mice with transgenic 
expression of a fragment of the human gene encoding 
CD1a on LCs demonstrated that LCs can present lipid 
antigens to effector T cells in the skin and amplify the 
inflammatory response in allergic contact dermatitis 
and psoriasis59. These reports suggest the diverse poten-
tial of LCs as APCs in the skin. Furthermore, the loss 
of MHC class I on radioresistant cells led to impaired 
granzyme B production in CD8+ T cells in the elicitation 
phase of CHS60, suggesting the possible involvement of 
endothelial cells61 and keratinocytes62,63 as APCs in the 
skin, although in vivo evidence for this remains lack-
ing. As co-stimulatory molecules are not required for 
activation of effector T cells64, various cells may carry 
out APC functions in the skin in a context-dependent 
manner (TABLe 1).
iSALT formation around postcapillary venules. 
Recently, a leukocyte-clustering structure named 
iSALT was proposed to serve as a site for efficient anti-
gen presentation in the skin20 (Fig. 5). Around 1980, the 
antigen-presenting capability of the skin was identified 
and people offered the term skin-associated lymphoid 
tissue (SALT) to describe this function65–67. Although 
SALT is a conceptual term, iSALT is an actual structure 
that transiently appears around postcapillary venules in 
response to various immunogenic stimuli, including hap-
tens and infection68,69. The iSALT is composed of various 
types of leukocytes, including perivascular macrophages, 
dermal DCs and T cells20. After hapten application to the 
skin, dermal DCs exhibit cluster formation around post-
capillary venules within hours. IL-1α produced by kerat-
inocytes in response to external insults activates M2-like 
macrophages around postcapillary venules, which then 
produce CXCL2 and recruit dermal DCs to the cluster. 
Leukotriene B4 (LTB4), a lipid mediator, also mediates 
the cluster formation by promoting DC migration70. 
Subsequently, effector T cells accumulate in the cluster 
and are presented antigens by dermal DCs, leading to 
their proliferation and activation. In the cluster, both 
major dermal DC subsets71, namely, CD11b+ dermal 
DCs and CD103+ dermal DCs, are detected72. It is cur-
rently unclear, however, which dermal DC subsets medi-
ate antigen presentation in the cluster60. Each DC subset 
in the cluster may work in a compensatory manner 
D
er
m
is
Hapten (FITC) Protein antigen
FITC–OVA Claudin 1 DAPI
Ep
id
er
m
is
D
erm
is
Epiderm
is
Tight
junction
Fig. 4 | Penetration of hapten and proteins into the skin. A hapten (fluorescein 
isothiocyanate (FITC); molecular mass = 389; left) or FITC-conjugated ovalbumin (FITC–
OVA ; molecular mass = 66 kDa; right) were painted onto the ear skin. After 24 hours, the 
ears were harvested and sliced. Nuclei (blue) and claudin 1 (red) were visualized. FITC 
distributed into the dermis (left), probably mainly through the hair follicles and cracks in 
the stratum corneum, while FITC–OVA remained outside the tight junctions (right). DAPI, 
4′,6-diamidino-2-phenylindole.
Box 3 | Antigen presentation in skin neoplasms
Antigen presentation by antigen-presenting cells and the subsequent activation of 
cytotoxic CD8+ T cells in the tumour site are essential for antitumour immunity. 
The blockade of programmed cell death 1 (PD1) signalling is believed to exert antitumour 
effects by inducing CD8+ T cell activation in the tumour52,91. In cancer, tumour-associated 
macrophages, CD11b+ dermal dendritic cells (DCs) and CD103+ dermal DCs can interact 
with CD8+ T cells and restrict the motility of the cells92,93. In melanoma, however, it has 
been reported that only CD103+ DCs can effectively activate the CD8+ T cells in the 
tumour94,95. As CD103+ dermal DCs constitute only approximately 1% of the total tumour 
DCs, the trapping of CD8+ T cells by CD11b+ dermal DCs and tumour-associated 
macrophages would limit the chance for CD8+ T cells to meet CD103+ dermal DCs and be 
activated, which may lead to inefficient antitumour immune responses. Because 
tumour-associated macrophages express PD1, which inhibits phagocytosis and the 
tumour immunity of tumour-associated macrophages96, PD1 inhibitors may exert their 
antitumour effects by affecting tumour-associated macrophages.
Trogocytosis
Lymphocytes that conjugate to 
antigen-presenting cells 
sometimes ‘rob’ the surface 
molecules and express them 
on their own surfaces. ‘Trogo’ 
means ‘gnaw’ in greek.
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Sensitization Elicitation
CD103+ 
dermal DC
IFNγ
CD11b+
dermal DC
Skin-draining
lymph node
12–24 hours
Dermal 
DC Effector
T cell
a
b
• Antigen presentation
• Effector T cell 
differentiation
(Tc1 and/or T
H
1 cell)
Stratum
corneum
Stratum
granulosum
Stratum
spinosum
Stratum
basale
LC
Hapten
Epidermis
Dermis
Effector
T cell
CXCL2LTB4 Perivascular
macrophage
Postcapillary
venule
IL-1α
Migration
• Antigen presentation
• Effector T cell activation
Tight
junction
IFNγ
Oedema and�
vesicle formation
Dermal 
DC
• iSALT formation
• Effector T cell activation
Fig. 5 | A schematic view of the sensitization and elicitation phases 
of contact hypersensitivity. a | In the sensitization phase of contact 
hypersensitivity , haptens pass through the skin barrier (stratum corneum and 
tight junction) and are captured by cutaneous dendritic cells (DCs), including 
Langerhans cells (LCs) and dermal DCs. DCs, especially CD103+ dermal DCs, 
present antigens to naive T cells and induce the differentiation of effector 
T cells — most notably IFNγ-producing cytotoxic T cells (which have been 
referred to as Tc1 cells) and T helper 1 (TH1) cells — in the skin-draining lymph 
nodes. In the elicitation phase, haptens captured by dermal DCs are 
presented to effector T cells in the skin. The activated effector T cells produce 
IFNγ and elicit skin inflammation. b | Haptens induce IL-1α production from 
keratinocytes, which activates M2-type macrophages that are located 
around postcapillary venules. The activated macrophages then produce 
CXC-chemokine ligand 2 (CXCL2), which promotes the accumulation of 
dermal DCs. Leukotriene B4 (LTB4) also plays an important role in driving DC 
accumulation by increasing DC motility. Effector T cells are activated within 
the DC clusters (present in inducible skin-associated lymphoid tissue (iSALT)) 
and produce cytokines.
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26 | JANuARY 2019 | volume 19 
like DCs in the sensitization phase73. Nevertheless, 
the blockade of CXCL2 and IL-1 receptor signal-
ling impairs the formation of leukocyte clusters 
and effector T cell activation, indicating that iSALT 
is an essential structure for antigen presentation 
in mouse CHS responses. An interesting remaining 
question is the role of iSALT in inflammatory skin dis-
eases other than allergic contact dermatitis. In fact, in 
psoriasis, an iSALT-like structure has been reported 
in the skinlesions in humans74. Therefore, iSALT may 
serve as an important structure that supports the devel-
opment of immune responses in other inflammatory 
skin diseases.
iSALT and other tertiary lymphoid structures. Under 
some pathological circumstances such as infection, 
chronic inflammation and cancers, lymph node-like 
structures called tertiary lymphoid structures (TLSs) 
have been detected in various non-lymphoid tissues75. 
In the lung, for example, leukocyte clusters called induc-
ible bronchial-associated lymphoid tissue (iBALT) are 
formed after pulmonary inflammation or infection76. 
iBALT can support the priming of naive B cells and 
T cells and also maintain memory B cell and T cell popu-
lations. Thus, iBALTs are considered essential structures 
that support rapid and efficient immune responses in the 
lung against some pathogens.
TLSs seem to play important roles in host protec-
tion against external antigens and also against internal 
antigens in the development of pathogenic conditions 
such as autoimmune diseases and cancers75,77,78. The 
TLSs involved in skin immune responses have not yet 
been clearly defined, but in order to be considered bona 
fide TLSs, they should show several of the following 
characteristics: the existence of distinct T cell and B cell 
compartments, the presence of a follicular reticular 
cell (FRC) network, the expression of peripheral node 
addressin (PNAd)+, the presence of high endothelial 
venules (HEVs) and a lymphatic vasculature, and evi-
dence of B cell class switching77. Most TLSs are not 
genetically programmed and do not develop postnatally. 
Instead, cytokines (lymphotoxin and TNF), lymphoid 
chemokines (CCL19, CCL21 and CXCL13) and recep-
tor activator of nuclear factor-κB ligand (RANKL; also 
known as TNFSF11) play crucial roles in the develop-
ment of TLSs. The characteristics of each leukocyte 
cluster are summarized in TABLe 2.
On the basis of these structural criteria, iSALT may 
not be classified as a TLS because of the absence of 
B cells, naive T cells, HEVs and the FRC network and 
the involvement of lymphoid chemokines have not 
yet been described in iSALT. However, from a func-
tional point of view, iSALT possesses the key feature 
of TLS in that it is an efficient site for effector T cell 
activation; some researchers thus use the term TLS 
for iSALT, focusing on this point78,79. Leukocyte clus-
ters are also reported in the genital mucosa after HSV 
infection and have been named ‘memory lymphocyte 
clusters’80. They are mainly composed of CD11c+ MHC 
class II+ cells and CD4+ memory T cells and do not con-
tain PNAd+ HEVs or lymphatic vessels. CD4+ memory 
T cells are recruited and maintained in the cluster 
through CCL5 produced by macrophages. In the mem-
ory lymphocyte clusters, CD4+ T cells rarely recirculate 
into the blood and are critical for preventing the local 
reinfection of HSV.
iSALT formation in human skin. It remains unclear 
whether iSALT is formed in human skin and supports 
T cell activation in an analogous manner to that seen 
in mice. Although iSALT-like structures (perivascular 
leukocyte infiltrations) are frequently observed by histo-
logical examination in many inflammatory skin diseases, 
these may simply reflect the extravasation process of leu-
kocytes, and it is not clear whether activation of effector 
T cells actually occurs in these structures. However, in 
some inflammatory skin diseases, this structure may 
serve as an iSALT by presenting antigens to effector 
T cells. In allergic contact dermatitis, DC–T cell clusters 
are found in the dermis and are accompanied by vesi-
cle formation, a marker of inflammatory cytokine pro-
duction in the epidermis above the cluster that suggest 
Table 1 | Putative APCs in the skin under different pathological conditions
Disease model Putative antigen-presenting cells in the skin
Contact hypersensitivity Dermal DCs20, mast cells56, blood endothelial cells61, 
radioresistant cells60 or LCs73,97
Graft versus host diseases LCs58 or keratinocytes63
Psoriasis Dermal DCs98 or LCs59
DC, dendritic cell; LC, Langerhans cell.
Table 2 | Characteristics and comparison of leukocyte clusters
Characteristic Type of leukocyte cluster
iSALT Memory 
lymphocyte clusters
iBALT
Presence of HEVs, lymphatic vessels and FRC No No Yes
Mediators involved in formation CXCL2, IL-1α 
and LTB4
CCL5 and CXCL9 Lymphotoxin, IL-17 , TNF, 
CCL19, CCL20 and CXCL13
Supports priming of naive T cells and B cells No No Yes
Supports reactivation of effector T cells Yes Yes Yes
Existence in human Unknown Unknown Yes
CCL , CC-chemokine ligand; CXCL , CXC-chemokine ligand; FRC, follicular reticular network; HEV, high endothelial venule; 
iBALT, inducible bronchial-associated lymphoid tissue; iSALT, inducible skin-associated lymphoid tissue; LTB4, leukotriene B4; 
TNF, tumour necrosis factor.
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that the activation of T cells occurs at the cluster20. In 
psoriasis, the existence of HEVs has been reported81, 
and clusters of DC-LAMP (also known as LAMP3)+ DCs and 
T cells have been detected in the dermis74 with abundant 
expression of CCL19 and CCL20 (ReFs82,83). This cluster 
disappears after treatment with TNF inhibitors74, sug-
gesting the involvement of TNF in the maintenance of 
the cluster. iSALT-like structures with CXCL13+ cells 
have been reported in the skin lesions of patients with 
secondary syphilis infections69. In melanoma, clus-
ters with TLS features, such as the existence of HEVs, 
T cells, B cells and mature DCs, have been detected in 
the extratumoural area and are associated with tumour 
regression or favourable overall survival in patients84,85. 
Lymphoid follicles are created in the skin lesions of 
cutaneous lupus erythematosus86 or Kimura disease87. 
Thus, although the functional importance of the leu-
kocyte clusters or lymphoid follicles in the skin remains 
unclear, these structures may play important roles in the 
promotion or regulation of disease development (TABLe 3).
Conclusions and perspectives
The skin is a barrier organ that separates the body 
from the external environment. The skin consists of 
three main parts: the epidermis, dermis and subcuta-
neous tissues. Each constituent has unique cells and 
structures, including immune cells and non-immune 
cells, which induce various immune responses to 
external stimuli in a coordinated manner. Substantial 
progress has been made in understanding the func-
tions of the different cell types in the skin and the 
mechanisms that they use to communicate harmoni-
ously. In particular, the understanding of the roles of 
non-immune cells, such as vascular cells and neurons, 
has shed light on the complexity of skin immunity and 
diseases. In addition, the identification of key loca-
tions and/or structures, such as hair follicles, perivas-
cular extravasation units and iSALT, has improved 
the understanding of cutaneous immune responses 
(Fig. 6). Moreover, it is now known that commensal 
and pathogenic bacteria directly regulate the func-
tional properties of skin immune cells, which has pro-
vided new paradigms that highlight the importance of 
host–microorganism interactions.
Despite such progress, we still lack a comprehen-
sive understanding of the skin in health and disease. 
Table 3 | Leukocyte clusters in human diseases in skin or genital mucosa
Disease Characteristics of the clusters Refs
Contact dermatitis Clusters of CD3+ cells and CD11c+ cells below 
epidermal vesicles
20
Psoriasis Existence of DC-L AMP+ DCs and T cells with 
CCL19 and CCL20 expression in the clusters
83
Secondary syphilis Existence of CXCL13+ fibroblast-like cells 69
HSV infection (skin) Variable numbers of CD30+ or CD56+ cells 99
HSV infection (genital 
mucosa)
Existence of CCR5+CD4+ T cells contiguous to 
CD123 or DC-SIGN+ DCs
100
Chlamydia trachomatis 
infection (genital mucosa)
Germinal centre formation 101
Kimura disease Germinalcentre formation 87
Cutaneous lupus 
erythematosus
Existence of plasmacytoid DCs 86,102
CCL , CC-chemokine ligand; CCR5, CC-chemokine receptor 5; CXCL13, CXC-chemokine 
ligand 13; DC, dendritic cell; HSV, herpes simplex virus.
Epidermis
Dermis
Hair follicles
• Recruitment of immune cells 
(LCs and T cells)
• Memory T cell responses 
(T
RM
 cells)
• Immune privilege 
(T
reg
 cells)
Postcapillary venules
• Formation of iSALT (transient 
effector T cell activation)
• Formation of perivascular 
extravasation units (neutrophil 
extravasation)
Fig. 6 | Newly identified key locations and structures in skin immunity. Hair follicles serve as locations for immune cell 
recruitment and create structures for memory T cell response as well as immune privilege. Inducible skin-associated 
lymphoid tissue (iSALT) and perivascular extravasation units are formed around postcapillary venules, which induce the 
transient activation of effector T cells and neutrophil activation, respectively. LC, Langerhans cell; Treg cell, regulatory T cell; 
TRM cell, resident memory T cell.
Kimura disease
A chronic inflammatory 
disorder characterized by a 
painless lymphadenopathy or 
masses on head and neck 
regions.
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28 | JANuARY 2019 | volume 19 
We do not exactly understand which immune cells and/or 
non-immune cells interact with each other and at which 
immune response time points these interactions occur 
(for example, during the acute, chronic and resolution 
stages of inflammation); we also do not know the pre-
cise anatomical locations of these interactions in the 
skin. Considering the fundamental differences between 
mouse and human skin is another important challenge. 
Evaluation of these points may lead to a breakthrough in 
the understanding of the immunological mechanisms of 
various cutaneous immune responses and healthy skin 
homeostasis.
Published online 14 November 2018
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Acknowledgements
This work was supported by grants from the Japan Society for 
the Promotion of Science KAKENHI (JP15K09766, 
JP15H05096 (to T.H.) and 263395 (to K.K)), Grants-in-Aid 
for Scientific Research (15H05790, 15H1155 and 
15K15417 to K.K.) and the Japan Agency for Medical 
Research and Development (AMED) (16ek0410011h0003 
and 16he0902003h0002 to K.K.). The authors thank A. 
Hayday of the King’s College London School of Medicine, 
London, UK, and E. Epstein Jr of PellePharm for the critical 
reading of the manuscript.
Author contributions
All authors contributed to the discussion of the content of the 
article. G.E. and T.H. also contributed to researching data and 
the writing of the article. K.K. and F.G. also contributed to the 
review and editing of the manuscript.
Competing interests
The authors declare no competing interests.
Publisher’s note
Springer Nature remains neutral with regard to jurisdictional 
claims in published maps and institutional affiliations.
Reviewer information
Nature Reviews Immunology thanks B. Malissen and the 
other anonymous reviewer(s) for their contribution to the peer 
review of this work.
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30 | JANuARY 2019 | volume 19 
	The immunological anatomy of the skin
	Stratum corneum
	Immunological anatomy of the epidermis
	Monocyte interaction with hair follicles. 
	T cell interaction with hair follicles. 
	Immune modulation by sebaceous glands. 
	Influence of the skin microbiota. 
	Immune responses in the dermis
	Immune modulation by dermal blood vessels. 
	Neuro-immune interactions in the skin. 
	Contact hypersensitivity responses
	Immunity in subcutaneous adipose tissue
	Skin anatomy and induction of adaptive immunity
	Antigen presentation by cutaneous APCs. 
	Antigen presentation in skin neoplasms
	iSALT formation around postcapillary venules. 
	iSALT and other tertiary lymphoid structures. 
	iSALT formation in human skin. 
	Conclusions and perspectives
	Acknowledgements
	Fig. 1 Physical and immunological barrier of the skin.
	Fig. 2 A specific contribution of postcapillary venules in cutaneous immunity.
	Fig. 3 Neuro-immune interactions and perivascular adipose tissue in the skin.
	Fig. 4 Penetration of hapten and proteins into the skin.
	Fig. 5 A schematic view of the sensitization and elicitation phases of contact hypersensitivity.
	Fig. 6 Newly identified key locations and structures in skin immunity.
	Table 1 Putative APCs in the skin under different pathological conditions.
	Table 2 Characteristics and comparison of leukocyte clusters.
	Table 3 Leukocyte clusters in human diseases in skin or genital mucosa.