REVIEW
Mechanisms of UV-induced immunosuppression
Thomas Schwarz
Department of Dermatology, University Kiel, Kiel, Germany(Received for publication on March 23, 2005)(Revised for publication on July 22, 2005)(Accepted for publication on August 24, 2005)

Abstract. Ultraviolet radiation (UV ), in particular the UVB range, suppresses the immune system inseveral ways. UVB inhibits antigen presentation, induces the release of immunosuppressive cytokinesand causes apoptosis of leukocytes. UVB, however, does not cause general immunosuppression but
rather inhibits immune reactions in an antigen-speciﬁc fashion. Application of contact allergens onto
UV-exposed skin does not cause sensitization but induces antigen-speciﬁc tolerance since such an individual cannot be sensitized against the very same allergen later, although sensitization against otherallergens is not impaired. This speciﬁc immunosuppression is mediated by antigen-speciﬁc suppressor/
regulatory T cells. UVB-induced DNA damage is a major molecular trigger of UV-mediated immunosuppression. Reduction of DNA damage mitigates UV-induced immunosuppression. Likewiseinterleukin-12 which exhibits the capacity to reduce DNA damage can prevent UV-induced immunosuppression and even break tolerance. Presentation of the antigen by UV-damaged Langerhans cells in
the lymph nodes appears to be an essential requirement for the development of regulatory T cells.
Studies addressing the molecular mechanisms underlying UV-induced immunosuppression will contribute to a better understanding how UV acts as a pathogen but on the other hand can be also used asa therapeutic tool. (Keio J Med 54 (4): 165–171, December 2005)
Key words: immunosuppression, immunotolerance, photoimmunology, regulatory T cells, ultraviolet
radiation

More than 25 years have passed since the discovery
that ultraviolet (UV) radiation can affect the immune
system. Since then numerous studies in the ﬁeld ofphotoimmunology have tried to identify the biological impacts of UV-induced immunosuppression. The
immuno suppressive effects of solar radiation are
mediated mostly by the middle wave length range(UVB, 290–320 nm). Therefore, the vast majority ofphotoimmunologic studies utilized UVB. There is also
recent evidence that the long wave range (UVA, 320–
400 nm) can affect the immune system although its
effects are less pronounced. To better understand thebiological impact of UVB radiation on human health,great efforts were made to identify the molecularmechanisms underlying UVB-induced immunosuppression.

UV Causes a Local and Systemic Form of
Immunosuppression
First evidence that UV radiation inﬂuences the immune system provided the observation that UV radiation inhibits the immunologic rejection of transplanted
tumours. Skin tumours induced by chronic UV exposure in mice are highly immunogenic since they are
rejected when transplanted into naive syngeneic hosts.1
However, when the recipient mice were given immunosuppressive drugs, the injected tumours were notrejected but grew, implying that the rejection is immunologic in nature. Rejection was also prevented when
the recipient animals received instead of immunosuppressive drugs an exposure to UVB radiation. This
clearly indicated that UV radiation can act in a similarmanner like immunosuppressive drugs.

Reprint requests to: Dr. Thomas Schwarz, Department of Dermatology, University Kiel, Schittenhelmstrasse 7, D-24105 Kiel, Germany, e-mail:tschwarz@dermatology.uni-kiel.de
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Schwarz: Photoimmunology

The same phenomenon can be observed in anotherimmunologic in vivo model, the induction of contact
hypersensitivity (CHS). CHS represents a special kindof delayed type hypersensitivity response which isinduced by epicutaneous application of contact allergens. To fully develop their antigenic features, thesereactive, low molecular weight substances have to bindto proteins and thus are called haptens. Painting of
haptens on skin areas which have been exposed to low
doses of UVB radiation does not induce CHS, whereas
administration of the same compound to a non-UVexposed site induces a normal CHS response.2 Inhibition of the induction of CHS by UV radiation is clearly
associated with a depletion in the number of Langerhans cells at the site of exposure.2,3 Langerhans cells
are the primary antigen presenting cells in the skin,
implying that UV radiation interferes with antigen presentation. Since in this experimental setting the contact
allergen is applied to the same area which receives the
UV exposure this type of immunosuppression is called
local.
Higher UV doses also affect immune reactions
induced at a distant, non-UV-exposed site. Accordingly, CHS cannot be induced in mice which are exposed to high doses of UV radiation even if the contact
allergen is applied at an unirradiated site.4 This type iscalled systemic immunosuppression. Systemic immunosuppression is certainly mediated by other mechanisms
than local immunosuppression. The question how
UV radiation can interfere with the induction of an immune response at a distant non-UV-exposed skin area
remained unanswered for quite a long time. Nowadays
it is clear that UV radiation stimulates keratinocytes torelease immunosuppressive soluble mediators includinginterleukin (IL)-10 which enter the circulation andthereby can suppress the immune system in a systemic
fashion (see below).
UV Radiation Affects Antigen Presentation
Since Langerhans cells are the major antigen presenting cells in the skin,5 depletion of Langerhans cells
by UVB seems to be responsible for the inhibition of theinduction of CHS following UV exposure.2 Dependingon the UV dose applied the disappearance of Langerhans cells may be due to the emigration of Langerhans
cells out of the epidermis since Langerhans cells harbouring UV-mediated DNA damage can be detected in
the draining lymph nodes.6 Higher doses of UV certainly induce apoptotic death of Langerhans cells. In
addition, UV radiation suppresses the expression ofmajor histocompatibility (MHC) class II surface molecules and adenosinetriphosphatase (ATPase) activity in
Langerhans cells.3 Both markers, in particular MHC
class II, are used to identify Langerhans cells in theepidermis. Furthermore, upon UV exposure Langerhans cells are impaired in their capacity to present
antigens.7 Inhibition of the expression of the adhesion
molecule ICAM-1 by UV radiation may be responsiblefor impaired clustering between Langerhans cells and T
cells. Accordingly, inhibition of antigen presentation by
UV radiation was proven both in vitro and in vivo. Injection of antigen-loaded Langerhans cells or dendritic
cells which had been exposed to UV radiation does not
result in sensitization, while injection of antigen-pulsed
cells mounts an immune response.8
Other antigen presenting cells including humanperipheral blood-derived dendritic cells and splenic
dendritic cells when exposed to UV either in vitro or invivo are also signiﬁcantly impaired in their ability tostimulate allogeneic T cells. UV radiation suppresses theexpression of the costimulatory B7 surface molecules(CD80/86) which are expressed on antigen presenting
cells and crucial for the interaction with T cells. Accordingly, UV radiation down-regulates the expression of
CD80 and CD86 on human Langerhans cells and on
blood-derived dendritic cells.9,10 Recently, it was discovered that UVB also induces reactive oxygen species
which may also contribute to impairment of the functionof antigen presenting cells by UV radiation.11 Antigen
presentation, however, may also be impaired indirectlyby the photoproduct cis-urocanic acid and by immunosuppressive cytokines or neuropeptides (see below).
UV Radiation Induces Immunologic Tolerance
Painting of contact allergens onto UV-exposed skindoes not result in the induction of contact hypersensitivity but induces tolerance, since application of thesame hapten several weeks later again does not induce
CHS.2 This indicates that the initial application of
the hapten onto UV-exposed skin induces long-term
immunologic unresponsiveness. However, immune
responses against other unrelated haptens are not suppressed which excludes that the animals were generally
immunosuppressed by the initial UV exposure. This
also implies that the immunologic unresponsivenessinduced by UV radiation is hapten-speciﬁc, a phenomenon called hapten-speciﬁc tolerance. Induction of UVmediated tolerance cannot only be observed in local but
also systemic immunosuppression.12 UV-induced tolerance appears to be mediated via the generation of
hapten-speciﬁc T suppressor cells, nowadays renamed
regulatory T cells.
UV Radiation Induces T Cells with Regulatory/
Suppressor Activity
Hapten-speciﬁc tolerance induced by UV radiation
appears to be mediated via the generation of T cells

Keio J Med 2005; 54 (4): 165–171

with inhibitory/suppressive activity. Injection of splenocytes from mice which had been tolerized by the application of a hapten onto UV-exposed skin into naı̈vesyngeneic mice rendered the recipients unresponsiveness to this particular antigen.13 Transfer of tolerance
can be observed both in the local13 and in the systemic
model.14 Although the transfer of UV-mediated suppression was subsequently shown in a convincing fashion in a variety of different immunological in vivo
models, the phenotypic characterization of the postulated UV-induced suppressor T cells was stuck formany years which contributed to the rejection of theconcept of suppressor T cells in general immunology.
Nowadays the concept of active suppression is unanimously accepted in general immunology, but the term
regulatory T cells is preferred to the term suppressor T
cells.
For the ﬁrst time Shreedar et al. succeeded in isolating T cell clones from UV-exposed mice, which weresensitized against ﬂuoresceine isothiocyanate.15 Cloned
cells were CD4þ , CD8 , TCR-a/bþ , MHC restricted
and speciﬁc for ﬂuoresceine isothiocyanate. They produced IL-10, but not IL-4 or interferon (IFN)-g. These
T cells blocked antigen presenting cell functions andIL-12 production and even more importantly, upon injection into naı̈ve recipients suppressed the induction of
CHS against ﬂuoresceine isothiocyanate.
Because of the existence of different UV-mediatedtolerance models (local, systemic, high dose, low dose)
different regulatory T cells with unique phenotypes
appear to be involved in these systems. Currently, best
characterized are the regulatory T cells involved in
the low dose suppression of CHS. Cells transferring
suppression in this model appear to belong to theCD4þ CD25þ subtype,16 they express CTLA-4,17 bindthe lectin dectin-218 and in contrast to the classicalCD4þ CD25þ T cells release high amounts of IL-10
upon antigen-speciﬁc activation.17 These cells may
represent a separate subtype of regulatory T cells since
they exhibit characteristics of naturally occurring regulatory T cells e.g. expression of CD4 and CD25 but alsoof type 1 regulatory T (Tr1) cells e.g. release of IL-10.19
While intravenous injection of T cells from UVtolerized mice into naive animals renders the recipientsunresponsive to the respective hapten, intravenous injection of the same cells into sensitized mice does notinhibit the CHS response in these recipients.20 This
gave rise to the speculation that regulatory T cells
inhibit the induction but not the elicitation of CHS
and thus are inferior to T effector cells. However, whenregulatory T cells were injected into the area of challenge of sensitized mice, the elicitation of CHS was
suppressed in a hapten-speciﬁc fashion.16 But whenears of oxazolone-sensitized mice were injected withdinitroﬂuorobencene-speciﬁc regulatory T cells and167

painted with dinitroﬂuorobencene before challenge withoxazolone, CHS was suppressed, indicating if once regulatory T cells are activated antigen-speciﬁcally they
suppress in an antigen-independent fashion. This phenomenon is named bystander suppression and has been
initially described for type 1 regulatory T cells (Tr1).
UV-induced regulatory T cells express the lymph node
homing receptor L-selectin but not the ligands for theskin homing receptors E- and P-selectin. Thus, UVinduced regulatory T cells though principally being able
to inhibit T effector cells do not suppress the elicitationof CHS upon intravenous injection since they obviously
do not migrate into the skin. Because of the capacity of
by-stander suppression, speculations exist about thetherapeutic potential of regulatory T cells which could
be generated in response to antigens known to bepresent in the target organ that are not necessarily theprecise antigen that drives the pathogenic response.21
However, these ﬁndings indicate that this strategy will
only be successful if the regulatory T cells home to thetarget organ. The unique migratory behavior of regulatory T cells might explain why in the vast majority of invivo studies upon intravenous injection regulatory T
cells have the capacity only to prevent but not to curevarious diseases.
IL-12 has been described by several groups to beable to prevent the suppression of CHS by UV, to prevent the development of regulatory T cells and even to
break UV-induced tolerance by yet unknown mechanisms.22–24 Since reduction of UV-induced DNA damage is associated with mitigation or loss of UV-induced
immunosuppression, DNA damage is regarded as the
major molecular trigger of UV-mediated immunosuppression.25,26 The prevention of UV-induced immunosuppression by IL-12 may be due to its recently described capacity to reduce DNA damage via inductionof DNA repair27 since the preventive effect of IL-12 is
not observed in DNA repair deﬁcient mice.6 UVinduced DNA damage appears to be also an importanttrigger for the induction of UV-induced regulatory T
cells. This assumption is based on the observation that
reduction of DNA damage containing Langerhans cells
in the regional lymph nodes by IL-12 prevents the development of regulatory T cells.6 Again, in DNA repair
deﬁcient mice, IL-12 failed to prevent the development
of UV-induced regulatory T cells.
UV-induced regulatory T cells also appear to play
an important role in photocarcino genesis. Although
their crucial role in supporting the development of UVinduced skin tumors has been already described in theeighties,28 these cells have been characterized only
recently. They appear to belong to the natural killer T
cell (NKT) lineage since they express the T cell marker
CD3 but also the NK marker DX5.29 After UV exposure these CD3þ DX5þ cells, which produced high168

Schwarz: Photoimmunology

amounts of IL-4, suppressed upon transfer antigenspeciﬁcally delayed-type hypersensitivity responses andantitumoral immunity against highly immunogenic UVinduced skin tumors in recipient mice.
UV Radiation Induces the Release of
Immunosuppressive Mediators
The ﬁnding that mice which are exposed to higher
doses of UV radiation cannot be immunized even when
the antigen is applied on a skin area which was not UV
exposed4 clearly indicated that UV radiation has to exert the capacity to suppress the immune system in asystemic fashion. Keratinocytes have been recognized
as a rich source for a variety of soluble mediators
including immunostimulatory and pro-inﬂammatory
cytokines. Cytokine release by keratinocytes can be effectively induced by UV radiation.30 UV radiation,
however, can also stimulate the secretion of immunosuppressive mediators since intravenous injection ofsupernatants obtained from UV-exposed keratinocytes
into naive mice renders the recipients unresponsive
to hapten sensitization.31 Accordingly, UV-induced
keratinocyte-derived immunosuppressive mediators
may get into the circulation and inhibit immune reactions at skin areas not directly exposed to UV radiation,
explaining the phenomenon of systemic immunosuppression.
The major soluble player involved in systemic UVinduced immunosuppression appears to be IL-10.
Keratinocyte derived IL-10 the release of which isinduced by UV radiation32 abrogates the ability ofLangerhans cells to present antigens to Th1 clones andeven tolerizes them. Injection of IL-10 into the skinarea of hapten application prevents the induction of
CHS and induces hapten-speciﬁc tolerance.33 In turn,neutralization of IL-10 with an antibody in UVirradiated mice prevents systemic UV-induced suppression of the induction of delayed type hypersensitivity.34
Other soluble mediators involved in UV-induced
immunosuppression besides IL-10 are tumor necrosis
factor-a (TNF-a),35,36 IL-4,37 prostaglandin E2 ,37 calcitonin gene related peptide,38 a melanocyte stimulating hormone39 and platelet activating factor.40
Urocanic Acid is Involved in UV-induced
Immunosuppression
Urocanic acid (UCA) has been recognized as another chromophore in the epidermis to be involved in
UV-induced immunosuppression.41 UCA is a metabolic
product of the essential amino acid histidine. UCA
accumulates in the epidermis because keratinocytes lackthe enzymes required for catabolisation of UCA. Of thetwo tautomeric forms of UCA trans (E)- and cis (Z)-UCA the latter predominates in the epidermis. UV
converts trans- into cis-UCA. Removal of UCA by tape
stripping of the epidermis prevents UV-induced suppression of the induction of CHS, indicating that cisUCA is involved in photoimmunosuppression.42 Furthermore, injection of cis-UCA partially mimics theimmunoinhibitory activity of UV radiation.43 In turn,
antibodies directed against cis-UCA restore particularimmune responses after UV exposure.44 Cis-UCA also
inhibits the presentation of tumour antigens by Langerhans cells.45 This effect can be reversed by IL-12.46
In addition, injection of cis-UCA antibodies reduces
the incidence of UV-induced skin tumours in a photocarcino genesis model, suggesting a role of cis-UCA in
the generation of UV-induced skin cancer.46
UV Radiation Induces Immunosuppression
Also in Humans
The vast majority of photoimmunology studies were
performed in vivo in animal models, mostly in mice.
Although numerous in vitro studies have been donewith human cells, the question is obvious whether theﬁndings obtained in the animal models can be extrapolated to the human system. In fact, UV radiation
appears to suppress the induction of CHS in men. Even
tolerance can be induced although according to one investigation only in 10% of the individuals.47 Tolerance
was hapten-speciﬁc, since the individuals revealed pronounced CHS responses upon subsequent immunization with other, non-related haptens.47 Other studies
reported a higher proportion of subjects to develop
tolerance when the hapten was applied onto skin areas
exposed to erythemogenic UV doses.48 Nevertheless, acertain proportion of human individuals may exist
whose immune response will be compromised by UV
radiation. This suggests in analogy to the murine system
the existence of UV-susceptible and UV-resistant individuals. Whether UV-susceptible individuals are athigher risk for the development of skin cancer is not yet
clear. In any case, sensitivity to sunburn appears to be
associated with susceptibility to UV radiation-induced
suppression of cutaneous cell-mediated immunity inhumans.49 Very recently, UV-induced immunosuppression is increasingly used as a tool to evaluate thepotency of sunscreens.50,51
Biological Relevance of UV-induced
Immunosuppression
UV-induced immunosuppression is a highly complex
process in which several different pathways are
involved (Fig. 1). The biological implications of UVinduced immunosuppression may be several-fold. In avariety of experimental models it has been demon-

Keio J Med 2005; 54 (4): 165–171

Fig. 1 Several mechanisms are involved in UV-induced immunosuppression. Sensitization takes place when an antigen (Ag) ispresented by dendritic cells to CD4þ T lymphocytes carrying the appropriate T cell receptor (TCR) in association with major histocompatibility complex class II molecules (MHC). In addition, the interaction of costimulatory molecules e.g. B7 with CD28 is required.
UV radiation suppresses the expression of MHC II and of costimulatory molecules (e.g. B7). In addition, UV radiation stimulates keratinocytes to release immunosuppressive mediators like IL-10 and
TNF-a which are responsible for systemic immunosuppression. Furthermore, UV radiation converts trans-UCA into cis-UCA which also
exerts also immunosuppressive effects.

strated that UV radiation suppresses protective immune responses against viral, bacterial and fungal
infections. The most frequently used infectious agentsto study these phenomena are herpes simplex virus, listeria, leishmania, mycobacteria and candida.52 Basedon these studies there is no doubt that UV radiation cancompromise an immune response against these agents
both in a local and a systemic fashion. However, basedon daily clinical practice it is obvious that acute and severe exacerbations of infectious diseases following solar
exposure are extremely rare in humans. The only exception is the herpes simplex infection in which recurrences after solar exposure are frequently observed.
Therefore, at this stage, the clinical implications of UVinduced immunosuppression for infectious diseases may
be limited.
However, the immune system does not only protectfrom infectious agents but also from malignant cells.
Transformed cells in particular in the early stage can berecognized as ‘‘foreign’’ and attacked by the immune
system (tumour immunology). This may apply in particular for both non-melanoma skin cancer and malignant melanoma. Striking evidence exists for a strong169

correlation between the risk to develop skin cancer andimmunosuppression. Chronically immunosuppressedindividuals, like transplant patients exhibit a signiﬁcantly increased risk for skin cancer.53 This riskcertainly increases with the cumulative UV load. In addition, the negative impact of UV radiation on the hostdefence against skin tumours has been convincingly
demonstrated in various experimental animal models.
Furthermore, restoration or even enhancement of an
immune response e.g. by topical or systemic applicationof immunomodulators (interferons, imiquimod) has
turned out as a successful therapeutic strategy for thetreatment of skin cancer. All this clearly supports thenotion that the immunosuppressive impact of UV radiation may be much more relevant for carcinogenesis
than for the exacerbation of infectious diseases.
It is both obvious and striking that UV radiation at
rather low doses suppresses an immune response. Thus,
one may speculate that a certain degree of immunosuppression may be beneﬁcial. The skin is an organ
which is constantly exposed to potential allergens, inaddition, the skin is an organ which is prone to autoimmunity.54,55 Hence, it is tempting to speculate that acertain degree of constant immunosuppression by dailysolar exposure may prevent the induction of these immune responses. If this is the case remains to be clariﬁed in the future. However, even in the case this turns
out to be true, excessive and chronic solar exposure willremain one of the major environmental threats for human health.
Acknowledgments: This work was supported by grants of the German
Research Association (DFG, SCHW1177/1-1, SFB415/A16) and the
CERIES Award 2004.

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