Ultraviolet light and dendritic cells

ARTICLE

The ultraviolet (UV) spectrum is divided into UVC (200-280 nm), UVB (280-320 nm) and UVA (320-400 nm). Of these only UVB and UVA are of environmental significance since UVC is effectively absorbed by ozone in the earth's atmosphere. UVB wavelengths penetrate the epidermis and are almost completely absorbed in the upper dermis while UVA penetrates to the deep dermis.

Dendritic cells (DCs) are bone marrow-derived professional antigen-presenting cells (APCs) that are necessary for the initiation of immune responses [1]. They express high amounts of class II major histocompatibility complex (MHC) antigens and have a dendritic morphology. They can present haptenized peptides and activate antigen-specific CD8⁺ effector and CD4⁺ regulatory T cell subsets indicating that they may induce or down-regulate the antigen-specific cutaneous inflammation [2]. Langerhans cells (LCs) are located in a suprabasal position in human and murine epidermis. Following the application of skin-sensitizing haptens, LCs are stimulated to migrate, via the afferent lymphatics, to the draining lymph nodes (DLNs). During migration from the skin, they are subject to phenotypic and functional changes so that they become highly immunogenic and effective for inducing a primary immune response. Recently, a novel type of DC has been identified in the dermis of normal human and mouse skin [3-5]. These dermal DCs play an important role in the regulation of skin immune responses [6] and are able to process and present soluble protein antigens [7].

Studies on the immune effects of UV light have mostly concerned the UVB band since these wavelengths are the most effective in inducing skin cancers. However, the experimental model that attracts most attention in photoimmunology is the suppressive effect of UVB on the induction phase of contact hypersensitivity (CHS) reactions. By using this model, two forms of immunosuppression can be identified: local and systemic [8] (Fig. 1). The local immunosuppression is obtained when the chemical hapten is applied on the irradiated skin, and is probably initiated by a direct effect of UVB radiation on LCs, causing an impairment of their capacity to present antigen. The systemic immunosuppression is obtained with larger doses of UVB radiation when the chemical hapten is applied at a distant non-irradiated site, and is due to the release of soluble mediators from UV-exposed skin such as cis-urocanic acid (cis-UCA), cytokines, prostaglandin E2, and neurohormones.

UVB and Langerhans cells

Human LCs have been shown to be reduced in number [9] and morphologically altered after UVB exposure. Some reports have demonstrated reduced surface MHC class II expression on human LCs following low-dose UVB in vivo [9] but others have demonstrated retention in vitro [10]. Therapeutic doses of UVB deplete the human epidermis of MHC II-positive cells, and residual LCs show a small but significant increase in their surface density of MHC II molecules [11]. Recent data suggest that low doses of UVB radiation destroy the functional and morphological integrity of human LCs, and that these cells are rapidly replaced by monocytoid cells that mature in situ into normal-appearing LCs [12]. An important finding is that in vitro irradiated human LCs undergo apoptosis [13]. Whether this phenomenon occurs in vivo has still to be demonstrated but is quite conceivable. After a severe sunburn, LCs are replaced by circulating bone marrow derived precursors and by DCs migrating from hair follicles that have a partial deficiency of molecules important for T cell costimulation [14]. These results indicate that the human hair follicle may be a specialized immune compartment of the skin that serves as an intermediate reservoir of LC between the bone marrow and the epidermis, and that may play a critical role in immune surveillance [14].

Murine epidermis contains two distinct cell populations, which contribute to the skin immune system: LCs and dendritic epidermal T cells (DETCs). LCs are important in the induction of immunity against a wide range of antigens such as reactive haptens, viral and bacterial antigens, allo-antigens (skin graft rejection) and tumor-associated antigens. DETCs are bone marrow derived and are distinguished from LCs in that they bear gamma delta T cell receptors on their surface and are MHC class II negative. The functions of DETCs are still unclear. They can recognize a limited set of antigens and act as antigen presenting cells (APCs) for suppressor T lymphocytes (Ts) playing a role in maintaining the immunological integrity of skin. Thy-1⁺ DETCs have not been detected in human epidermis and are only found in rodent epidermis. I-J⁺ macrophages represent an other small population of murine APCs that express MHC class II determinants on their cell surface and that preferentially activate Ts. The human counterpart for I-J⁺ cells is thought to be a population of CD36⁺DR⁺CD11b⁺CD1a^­ cells that have been characterized primarily in human UV-irradiated skin [15, 16]. UVB radiation depletes both LCs and DETCs in a dose-dependent fashion but compared to LCs, the re-emergence of DETCs is delayed [17]. Mechanisms underlying the depletion of LCs and DETCs are still unknown. Chronic exposure to UVB radiation may cause the deficiency of relevant growth factors for LCs and DETCs [18]. Alternatively UVB may abrogate cytokine responsiveness of epidermal DCs by down-regulating the expression of surface receptors for growth factors [18]. The UVB-induced CSF-1 deficiency in the epidermal microenvironment and the downregulated surface expression of CSF-1 receptors on DCs may be relevant to the UVB-mediated loss of resident epidermal LCs in skin [19]. Lastly, UVB radiation may trigger apoptosis of LCs and DETCs through the generation of reactive oxygen intermediates or by causing the deficiency of soluble factors such as IL-7, that prevents DETC apoptosis [18]. The epidermal LC depletion is mostly due to migration since cells with UV-specific DNA damage are present in murine lymph nodes after in vivo UV irradiation [20]. This migration to the lymph nodes may be due to the UV-induced synthesis of epidermal or dermal TNFalpha [21, 22].

UVB and antigen presentation

UVB irradiation of human LC inhibits the capacity of these cells to induce CD4⁺ as well CD8⁺ T cells proliferation. The in vitro UVB-induced immunosuppression is not mediated by inhibitory soluble factors and may be associated with an impaired development of LC accessory function [23]. Furthermore, UVB interferes with the antigen-presenting capacity of epidermal cells by affecting both antigen processing by LCs and the production of keratinocyte-derived factors required for optimal T cell proliferative responses [24].

UVB radiation inhibits the antigen-presenting capacity of LC in vitro and the impairment of accessory molecules on LC by UVB plays a crucial role by altering the functional interaction between APCs and T cells. UVB can convert LCs from immunogenic to tolerogenic APCs by altering the functional activity of LCs or other accessory cells. Hence UVB may act directly on LCs by inhibiting costimulatory signals, thereby abrogating their capacity to stimulate antigen-specific CD4⁺Th1 cells [25], while they fully retain the capacity to activate Th2 cells [26]. These results indicate that UVB radiation reverses the preferential capacity of LC to activate Th1 over Th2 cells. This UV-induced modulation of the APC activity does not only constitute a prevention of antigen presentation but leads to an active induction of tolerance or anergy: Th1 cells do not proliferate with a subsequent antigenic stimulation but retain their capacity to proliferate in response to exogenous IL-2. The mechanisms through which UVB interferes with the ability of LC to bind to T cells or to deliver the necessary costimulatory signals remain to be determined. Attractive molecules for UVB-sensitive costimulatory factors are ICAM-1 and B7 molecules.

In vitro experiments clearly demonstrate that the UVB-induced inhibition of monocytes, accessory function is associated with a decrease in their surface membrane ICAM-1 expression [27]. Furthermore, doses of UVB radiation that inhibit LC accessory function and ICAM-1 expression are ultimately cytotoxic for murine epidermal LCs [28, 29]. These results suggest that irradiated LCs do not survive long enough in vivo to induce an efficient primary immune response and that once they reach DLNs, sublethal or apoptotic LCs do not deliver the adequate costimulatory signals to activate Th1 cells. The mechanism by which UVB radiation inhibits ICAM-1 expression by cultured LCs is uncertain. UVB could inhibit ICAM-1 gene expression by interfering with the synthesis or the activity of trans-activating factors that are required for enhanced transcription, or by causing structural alterations in the ICAM-1 gene itself [28].

B7-1 (CD80) and B7-2 (CD86) costimulatory molecules on dendritic cells and their counter receptors CD28 and CTLA-4 on T cells, are thought to be critical for successful antigen presentation [30]. B7 costimulation contributes to IL-2 production by both naive and previously activated CD4⁺ T cells. This signal is also critical for the differentiation of naive CD4⁺ T cells to IL-4 producers and for the development of cytotoxic T cells through both effects on T-helper cells and direct co-stimulation of CD8⁺cells [30].

UVB inhibits B7-1 and B7-2 upregulation on murine LC by acting directly on LC [31] and affects human LC by decreasing the culture-induced upregulation of B7.1 and B7.2 molecules [13, 32]. Keratinocyte-derived IL-10 or
IL-10 released from Th2 cells may further suppress antigen presentation for Th1 cells by decreasing CD80 [33], CD86 [34] and HLA-DR [35] expression at the dendritic cell surface. These in vitro studies should be interpreted with caution since a recent report demonstrates that in vivo solar-simulating radiation was associated with a transient upregulation (12 to 24 hrs after the irradiation) of B7 molecules on human epidermal LCs [36].

CD40 antigens are cell surface receptors that belong to the tumor necrosis factor receptor family. They are expressed on DCs, macrophages, mast cells, endothelial cells [37], keratinocytes [38] and human LCs [39]. These molecules may have an important costimulatory function through their interaction with their CD40L (CD154) ligand which is expressed on the surface of activated CD4⁺ T-helpers. CD40/CD40L interactions are involved in APC activation, T cell priming and effector T cell maturation. Furthermore, recent data indicate that CD40 ligation is crucial in the delivery of T cell help for cytotoxic T lymphocyte priming [40]. The effects of UV light on CD40 expression and CD40/CD40L interactions are still unknown but should be promptly assessed since these molecules are critical for T cell activation and are involved in vitro in the prevention of UV-induced apoptosis of human LCs [13].

Modulation of LC function by soluble factors

Contribution of soluble factors released from UV-exposed skin may modify directly or indirectly the function of APCs or of relevant T cells at the time of antigen presentation.

Urocanic acid (UCA) represents the major UVB-absorbing component of the skin. Trans-UCA is naturally produced in the stratum corneum and converts to the cis-isomer upon UVB irradiation. Although cis-UCA by itself has no direct effect on LC antigen-presenting function [41, 42] and does not act directly on LCs to induce their migration [43], many reports support the notion of cis-UCA as an important factor in the generation of UV-induced immunosuppression [44]. In fact, cis-UCA may impair the induction of CHS through a multi-step process by causing the local release of TNFalpha [45].

The capacity of the skin immune system to mount various types of immune response is largely dependent on its ability to release and respond to different signals provided by immunoregulatory mediators such as cytokines. The constitutive production of cytokines by keratinocytes is low but can be enhanced by UV exposure [46]. With regard to immunosuppression, three cytokines appear of particular interest: TNFalpha, IL-10 and IL-12.

TNFalpha is a multifunctional cytokine that has an important role in the pathogenesis of inflammation, lymphocyte activation and apoptosis [47]. UV exposure causes the release of TNFalpha that contributes to the apoptosis of keratinocytes [48] and to the migration and maturation of LCs [49].

IL-10 is a 18 kD cytokine, which was previously described as a product of murine Th2 cells and that inhibits the synthesis of several cytokines by Th1 cells. Of interest, this cytokine can interfere with antigen presentation by LC [50] and exhibits immunosuppressive properties [51, 52]. UVB light upregulates IL-10 production by murine and human keratinocytes [53-55] and there is evidence that keratinocyte-derived IL-10 is involved in systemic immunosuppression [53] and may inhibit the maturation process of emigrating epidermal LCs and converts them to tolerogenic APCs [56].

IL-12 is a recently discovered cytokine that has costimulatory effects on T helper cells by preferentially inducing Th1-specific immune responses and by inhibiting the development of Th2 cells. Activated macrophages, dendritic cells, B cells, neutrophils, Th1 lymphocytes and keratinocytes [57] are established sources of IL-12. This cytokine is the most critical factor for skewing the immune response towards a Th1 profile and somewhat counteracts the effects of IL-10. Indeed, recent studies showed that injection of IL-12 prevents UV-mediated suppression of CHS and breaks UV-induced hapten specific tolerance by inhibiting Ts belonging to the CD8 subtype [58-60]. The UVB-induced suppression of monocyte IL-12 production is responsible for the selective impairment of Th1 responses [61]. The IL-12 production by murine dendritic cells can be upregulated by CD40/CD40 ligand interaction and downregulated by IL-10 and IL-4 [62]. In turn, IL-12 may upregulate CD40L expression on activated human T cells [63].

If TNFalpha, IL-10 and IL-12 are key mediators of immunosuppression, UV light affects the release and the activity of other cytokines and growth factors that may be involved in UV-modulated immune responses [64]. Inflammatory mediators such as prostaglandins, which are released after UV-exposure, may modulate the cytokine production of dendritic cells and thereby influence their antigen presentation. Indeed, elevated levels of PGE2 promote in vitro a Th2 immune response by impairing the ability of human maturing DCs to produce IL-12 and by inducing them to produce high amounts of IL-10 [65].

There is recent evidence that neuropeptides such as alpha-melanocyte-stimulating hormone (alpha MSH), upon stimulation, are released by dendritic cells and keratinocytes [66]. Alpha MSH inhibits the production and activity of cytokines such as IL-1, IL-2, IFNgamma and downregulates the expression of B7 molecules on APCs; this neuropeptide is also a potent inducer of IL-10 that inhibits the induction of contact hypersensitivity responses and induces hapten-specific tolerance in murine models [66, 67]. Calcitonin gene-related peptide (CGRP) and nitric oxide, which inhibit antigen presentation by dendritic cells in vitro, may also be involved in UV-induced local immunosuppression [68]. CGRP released by UVB from cutaneous nerve endings, triggers mast cell release of TNFalpha that impairs CHS induction. Therefore CGRP may play an essential role in the loss of CHS induction after UV [69].

Mechanisms: apoptosis and pyrimidine dimers

Human LCs undergo apoptosis after in vitro UVB irradiation [13] and murine LCs become sensitive to apoptotic signals delivered by antigen-specific interactions with T cells [70]. The apoptosis known to occur after UVB irradiation might involve the Fas/Fas ligand (FasL) signaling pathway and the UV-induced Fas expression may serve to target stress-injured cells and to facilitate the apoptosis and elimination of harmful cells [71]. Furthermore the Fas/FasL system may play a crucial role in UV-induced tolerance since UV-induced Ts may act by inducing the cell death of APCs via the Fas pathway [72]. IL-12, which breaks UV-induced immunosuppression, may inactivate or inhibit Ts [60] and may interfere with the Fas/FasL system to prevent DC death induced by Ts [72]. Thus, the interactions between DCs and T cells may be greatly influenced by the UVB-induced apoptotic signals. DCs undergoing apoptosis may deliver unusual activation signals to T cells during antigen presentation, signals that lead to cellular unresponsiveness rather than to effective immunity [70].

UV-induced damage in cutaneous APCs is responsible for their impaired ability to present antigen after in vivo UV irradiation [73, 74]. DNA is the major target of UV irradiation in the generation of systemic immunosuppression and the primary molecular event mediating this type of immunosuppression is the formation of pyrimidine dimers [75]. Importantly, photosomes treatment and photoreactivating light that split UV-induced cyclobutane pyrimidine dimers allow the restoring of the APC function of UV-irradiated APCs [73]. Applications of liposomes containing an endonuclease reduce the induction of IL-10 by UV irradiation, indicating that DNA damage may trigger the production of cytokines that down-regulate immune responses initiated at distant sites [76]. However, DNA is not the only molecular cellular target for UV and evidence is accumulating that UV can also affect cytoplasmic and membrane structures such as transcription factors, kinases and membrane receptors [77].

UV-induced macrophages

Acute UVB irradiation of human skin results in an initial depression of the allogenic epidermal APC activity. However, this depression is transient and rapidly followed by the appearance of CD1a^­DR⁺ cells that restore the epidermal alloantigen presentation [15] (Fig. 1). These APCs display a different phenotype from resident LCs [16] and are potently induced in the epidermis after UVB and UVC, but not after UVA exposure [78]. Thus, high UVB doses create in vivo an epidermal and dermal APC milieu which is dominated by monocytic/macrophagic cells through depletion of both epidermal and dermal cells of dendritic APC phenotype, and concomitant selective dermal expansion of a CD1a^­DR⁺CD11b⁺CD36⁺Fc gammaRII⁺ monocyte/macrophage population [79]. UV-induced macrophages (UV-Mphs), in contrast to epidermal cells from normal skin, potently activate autologous CD4⁺ suppresssor-inducer T cells [80] and induce a dominance of functional T-suppressor cell activity [81]. These mechanisms may function to suppress responses to UV-induced autologous antigens that may trigger autoreactivity and autoimmune disorders. Alternatively, the suppressive immune response induced by UV-Mphs may also facilitate the growth of UV-induced skin cancers as it occurs in murine models. UV-Mphs that infiltrate the epidermis 72 hrs after UVB irradiation potently produce IL-10 mRNA and secrete IL-10 protein [82]. These monocytic/macrophagic cells with high IL-10 and low IL-12 expression initially appear in the dermis as early as 6 hrs after UVB-exposure, and then appear in the epidermis. Their activated status is acquired as a result of encountering UV-induced changes in the dermal microenvironment [83] and UV-Mphs as well as LCs may themselves be differently responsive to the surrounding inflammatory milieu which may in turn modulate their antigen-presenting or effector capabilities [84]. CD4⁺ T lymphocytes activated by UV-Mphs are, in contrast to LC-activated T cells,
IL-2Ralpha deficient [85]. The differences in costimulatory molecule expression, on UV-Mph and LC, are critical in determining the distinct T cell activation induced by these APCs. Indeed, in contrast to LC, UV-Mph displays a reduced capacity to upregulate the expression of important costimulatory molecules such as CD40, B7-1 and B7-2 [86].

UVB-irradiated murine epidermis is depleted of LCs and heavily infiltrated by neutrophils, differentiated macrophages, and monocytic antigen-presenting cells that are distinct from LCs in both phenotype and ultrastructure [87]. Among these populations, the class II MHC⁺ CD11b⁺Ia^­ subset is similar to UV-Mphs observed in human skin and appears to be responsible for the allo-antigen-presenting cell activity in the early period following UV injury [87]. DCs expressing macrophagic markers and lacking Birbeck granules are also found in DLNs of UV-irradiated mice sensitized by the application of fluorescein isothiocynate suggesting that a significant proportion of non-LC APCs in the DLNs may be derived from inflammatory cells that infiltrate the skin after UV irradiation [88]. CD11b⁺ UV-Mphs are responsible for locally-induced tolerance after UV exposure [89] and in vivo anti-CD11b treatment allows the restoration of the ability to induce a primary contact sensitivity response and blocks tolerance induction [90]. UV-induced activation of complement component 3 (C3) may play a role in the regulation of CHS responses and antigenic tolerance. Ligation of the leukocyte ß2 integrin CD11b by iC3b molecules formed from C3 activation in UV-exposed murine skin, may modify CD11b⁺ cells as these APCs are unable to sensitize in a primary immune response, but actively induce antigenic tolerance [91]. The function of UV-Mphs is still debated but one may speculate that these leukocytes may contribute, not only to tolerance, but also to acute phototoxicity and chronic photodamage [87].

UVB-induced suppression of allergic responses

UVB exposure as well as solar simulated UV exposure impairs the induction of CHS [92, 93] and promotes tolerance to epicutaneous antigens [92]. It is of interest to note that levels of UV-exposure below clinical detectability can impair immune responsiveness [92]. The UVB susceptibility in humans does not appear to be correlated with the number of LCs or UV-Mphs in the epidermis at the time of sensitization, neither with the capacity of LCs or UV-Mphs to activate in vitro T cells [94]. UV effects on DTH in humans may depend upon the duration of exposure. Hence, although short term irradiation with suberythemal doses of UV induces a significant suppression of Mantoux responses, a prolonged UV exposure fails to do so, indicating that adaptative mechanisms appear to counteract the immunosuppressive effects of chronic irradiations [95].

The CHS model has been widely used to explore the immune effects of UV light in mice. Acute low-dose UVB radiation impairs CHS induction in some strains of mice (called UVB-susceptible, UVB-S), but not in others (called UVB-resistant, UVB-R) [96]. The UVB susceptibility may be determined by the production within the irradiated epidermis of UVB-dependent soluble factors (TNFalpha, cis-UCA, alphaMSH or IL-10) that act directly on LCs and impair the LCs ability to induce CHS [97]. Alternatively, the traits of UVB-S and UVB-R can be expressed directly by LCs [98]. Low doses of UVB radiation that deplete the epidermis of LCs do not deplete the dermis of UVB-resistant mice of CHS-inducing APCs, but do confer upon dermal cells of UVB-susceptible mice the capacity to induce unresponsiveness [99]. Dermal mast cells are necessary for the induction of systemic suppression of murine CHS responses by UVB radiation, and mast cell-derived histamine and TNFalpha may be components of the UVB-induced systemic immunosuppression [100, 101]. Studies in experimental models support the hypothesis that UVB irradiation and cis-UCA suppress CHS responses to hapten by the induction of histamine, which in turn evokes a prostanoid-dependent component of immunosuppression [102].

CONCLUSION

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