Mechanisms involved in ultraviolet light‐induced immunosuppression

ARTICLE

Auteur(s) : François AUBIN

Department of Dermatology and Cell Biology, University Hospital, 2 Place Saint-Jacques, 25030 Besançon, France

Article accepted on 6/8/03

Experimental models of UVB-induced immunosuppression

Transplantation of UVB-induced skin tumor (Fig. 1)

UVB-induced skin tumors are highly immunogenic and are therefore rejected after transplantation into normal syngeneic mice. However, when the recipient mice were therapeutically immunosuppressed or UVB-irradiated, the UVB-induced skin tumors grew progressively [3]. In addition, UVB exposure can stimulate the in vivo growth of murine melanoma cells by impairing the local immune efferent response [7].

Contact (CHS) and delayed type (DTH) hypersensitivity reactions

According to the UVB dose used, two animal models have been developed: the “acute low-dose model” and the “high-dose model” [8]. Low-dose UVB irradiation induces inhibition of the local sensitisation phase of CHS response to a hapten applied to previously irradiated skin [9]. High-dose UVB irradiation induces inhibition of the systemic sensitization phase of CHS to the hapten and DTH to the alloantigen when antigen is applied or injected into distant non-irradiated skin respectively. Both local and systemic immunosuppression are genetically restricted, because only certain inbred strains of mice are susceptible (C3H/HeN, C57/BL6, Skh-1) to immunosuppressive effects of UVB, while other strains are resistant and develop normal immune responses after UVB irradiation. Furthermore, it has been demonstrated that polymorphisms in the TNF region confer susceptibility to UVB-induced impairment of CHS induction in mice and humans [10]. Both models are associated with the production of transferable hapten-specific T suppressor cells and with the induction of tolerance. In addition, intravenous injection into naive recipients of supernatants obtained from UVB-irradiated keratinocytes leads to the inhibition of both local and systemic CHS and DTH [11].

Chromophores

Urocanic acid

Urocanic acid (UCA) which is generated in the metabolic pathway of the essential amino acid histidine, accumulates in the stratum corneum, as epidermal cells lack the necessary enzymes to further catabolize UCA [12]. UCA exists in both isomeric forms, trans and cis. Trans-UCA is the predominant form in non-irradiated epidermis, and upon UVB irradiation, UCA is photoisomerized from trans- to cis-UCA. Injection of cis-UCA partially inhibits the immune response and removal of cis-UCA after epidermal stripping resulted in the inability of UVB to induce immune suppression [13]. Further studies confirmed the involvement of cis-UCA in alteration and in impairement of antigen-presenting function of LC, and thus in suppression of DTH to various infectious agents or CHS to hapten [12]. However, anti-cis-UCA antibodies only partially restore hapten-specific immune suppression after UVB [14], and cis-UCA is not able to induce the expression of immunosuppressive cytokines in murine keratinocytes [15].

DNA

In contrast to experiments with anti-cis-UCA antibodies, the repairing of UVB-induced DNA damage leads to complete restoration of the immune response after UVB exposure. Applegate et al. [16] were the first to demonstrate that repairing pyrimidin dimer in vivo blocks the induction of immune suppression of CHS. They used Monodelphis domestica, a marsupial with an endogenous light-activated DNA repair enzyme that, upon activation by visible light, is able to repair pyrimidin dimers. More recently, liposomes containing the bacteriophage excision repair enzyme, T4N5 were developped. When applied to the skin, the enzyme is delivered into the cytoplasm and the nucleus of keratinocytes and LC [17]. In addition, application of T4N5 significantly reduces the number of pyrimidin dimers and antagonizes the inhibition of systemic and local CHS or DTH responses [18]. There is also evidence that T4N5 blocks the induction of immune regulatory suppressor T cells [18] and the secretion of IL-10 and TNFα [19, 20]. Identical results were observed in human volunteers [21], and Stege et al. [22] confirmed these data using photolyase (a pyrimidin dimer-specific photoreactivating enzyme isolated from Anacystis nidulans) — containing liposomes. These findings strongly suggest that DNA damage plays a major role in UVB-induced immune suppression.

Lipid membranes (Fig. 2)

UVB may also affect cytoplasmic and membrane targets [23]. Membrane lipid peroxidation induced by UVB leads to the formation of free radicals which contribute to PAF activation [24]. Oxidizing phosphatidylcholine causes the formation of PAF-like lipids that bind to PAF receptors and activate cytokine synthesis [25]. UVB can directly trigger surface receptors and subsequently activate the Src tyrosine kinase [26]. This results in the activation of signal transducing proteins including H-Ras, Raf-1, C-jun, STAT-1 leading to the activation of transcription factors such as AP-1, NF-kB and IRF-1 [27-29]. These data indicate that nuclear and extranuclear signalling pathways are generated independently by UVB and have been recognized to be not mutually exclusive but to contribute to immunosuppressive effects of UVB in an independent and accumulative way [30].

Effects of UVB on the afferent phase of immune response

Langerhans cells

Langerhans cells (2 to 5 % of epidermal cells) are the major antigen-presenting cells of the epidermis. Toews et al. [9] were the first to report that low dose UVB radiation induces both numeric, morphological (Fig. 3), and functional alterations of epidermal Langerhans cells (LC). The dendritic network of LC is destroyed by UVB exposure. In addition, UVB radiation suppresses the expression of surface molecules, including ATPase activity, MHC class II and co-stimulatory molecules ICAM-1 and B7. All these alterations result in a profound depletion of epidermal LC which might account for the inhibition of the induction of CHS response in mice sensitised through UVB-irradiated skin. Depletion of epidermal LC following UVB irradiation can be explained by two mechanisms [31]: first, migration of structurally altered and functionally impaired LC from the epidermis to the regional draining lymph nodes has been demonstrated [32, 33]. Indeed, when fluorescein isothiocyanate (FITC) was applied to UVB-exposed skin, the draining lymph nodes contained Ia +, and FITC + cells with pyrimidin dimers suggesting a migration of sensitized UVB-irradiated epidermal LC. Another possibility is the induction of apoptosis in remaining epidermal LC [34, 35]. Furthermore, whereas normal LC present antigens equally well to type 1 T cells (Th1) and type 2 T cells (Th2), UVB-irradiated LC efficiently present antigen to Th2, but do not stimulate T cell clones of the Th1 type [36]. Ineffective antigen presentation by UVB-irradiated LC can be due to direct irradiation effect as demonstrated by the presence of UVB-specific DNA damages (pyrimidine dimers) within LC [32]. Another possibility is the induction of paracrine mechanisms by surrounding UVB-irradiated keratinocytes which release a large number of immune regulatory cytokines such as IL-10 [19, 37]. However, Vink et al. [38] using liposomes containing photolyase, a pyrimidin dimer-specific photoreacting enzyme, demonstrated that the UVB-induced DNA damage to epidermal LC was the initiating event in UVB-induced local suppression of CHS.

Other cutaneous cells

Beside epidermal LC, other dermal cells can provide antigen-presenting functions. Kurimoto et al. [39] have demonstrated that doses of UVB radiation that deplete the epidermis of LC transform dermal dendritic cells CD1a + into immunosuppressive and tolerogenic cells. In addition, acute UVB irradiation of human skin results in the induction of T-suppressor and tolerogenic CD1a-, DR +, CD11b +, CD36 + macrophages into human epidermis 72 hours, post-UVB exposure [40, 41]. These inflammatory macrophages are the major source of IL-10 in human UVB-irradiated epidermis, but they fail to secrete IL-12 [42], contributing thus to the induction of UVB-induced immune suppression and tolerance. It is also interesting to note that UVB irradiation activates the complement cascade into the epidermis [43] and particularly the third component of complement (C3b). Ligation of the macrophage β2 integrin CD11b by C3b molecules may transform CD11b + macrophages from efficient antigen-presenting cells into immunosuppressive and tolerogenic cells. As for LC, the expression of co-stimulatory molecules on macrophages and keratinocytes from UVB-irradiated skin is low, which may contribute to poor antigen-presenting activity [44, 45]. In addition to macrophages, a single exposure of normal human skin to UVB induces an infiltration of numerous IL-4 +, CD11b +, CD15 +, CD36- neutrophils in the dermis, which subsequently migrate into the epidermis [46]. To summarize, dynamic and reciprocal changes of CD11b + macrophages and neutrophils influx and CD1a + LC losses occur in human epidermis and dermis after in vivo UVB exposure [41, 42, 46]. Because IL-4 and IL-10 are strong Th2-polarizing cytokines, all these processes contribute to create an immunosuppressive state in the irradiated skin. Mast cells play also an important role in UVB-induced immune suppression [47]. However, the exact mechanism by which mast cells induce immune suppression is still unclear. It is possible that UVB radiation activates dermal mast cells to secrete immunosuppressive mediators, such as IL-10.

Draining lymph nodes

It is well established that draining lymph node (DLN) cells recovered from mice about 20 hours after sensitisation with epicutaneous application of a hapten can transfer CHS to the same hapten when injected into naive mice. The ability of DLN cells to induce CHS in recipient mice is due to the presence of dendritic Ia + antigen-presenting cells [48, 49]. On the other hand, injection of DLN cells, recovered from mice irradiated with UVB before sensitisation is unable to induce CHS [49]. Previous experiments indicated that in mice sensitised with the fluorescent hapten FITC on UVB-exposed skin, the draining lymph nodes contained Ia +, and FITC + cells with pyrimidin dimers [32]. Futhermore, when the DLN cells were isolated from mice exposed to UVB and immediately treated with T4N5 (a bacteriophage excision repair enzyme specific to UVB-induced pyrimidin dimers)-containing liposomes before sensitization to FITC, the number of pyrimidin dimers found in DLN cells was significantly decreased, and no immune suppression of CHS to FITC was noticed after injection of DLN cells [32]. These results suggest therefore that UVB exposure impairs the antigen-presenting activity of DLN cells most likely initiated by the formation of UV-induced pyrimidin dimers in the epidermis.

Effects of UV on the efferent phase of the immune response

Immune regulatory suppressor T cells

Although it has been known for more than 20 years that both systemic [50, 51] and local suppression [52] can be transferred by splenic T cells, the phenotype and mechanism of action of the suppressor T cells are not clearly understood. Using a model of local CHS to dinitrofluorobenzene which is mediated by CD8 + effector T cells and down-regulated by CD4 + T cells [53], Krasteva et al. [54] showed that UVB-induced immunosuppressive effects were mediated by CD4 + T cells since in the absence of CD4 + T cells (MHC class II-KO mice and CD4 + T cell-depleted mice), UVB had no suppressive effects. In addition, in the absence of CD4 + T cells, UVB did not alter the priming of MHC class I-restricted CD8 + effector cells and UVB-irradiated mice developped a normal CHS reaction to DNFB. The authors suggested that CD4 + T cells mediated the immunosuppressive effects of UVB through inhibition of expansion of hapten-specific CD8 + effector T cells in the lymphoid organs. Furthermore, UVB-induced CD3 +, CD4 +, and CD8 – suppressor T cells mediated their suppressive effects by releasing the immune regulatory cytokines IL-4 and IL-10 [55]. Two types of UVB-induced immune regulatory suppressor T cells are thus suggested. Moodycliffe et al. [56] recently demonstrated that CD3 +, CD4 +, DX5 +, T cell receptor intermediate expressing, IL-4 secreting, and CD1-restricted NKT cells, isolated from the spleens of UVB-irradiated mice, transfer suppression of tumor rejection and DTH reaction. It is thus possible that UVB-induced IL4-secreting NKT cells directly suppress effector cell function. However, another UV-induced suppressor T cell has also been identified in a murine model of UV-induced immune tolerance to hapten [57, 58]. In addition, the authors demonstrated that T cells transferring hapten-specific UV-mediated tolerance express CTLA-4, which is regarded as a negative regulatory T cell-associated molecule [58]. On in vitro expansion, CTLA-4 + T cells transferring suppression secrete high levels of IL-10, TGFβ, and IFN1α and low levels of IL-2 but no IL-4, similar to a T regulatory 1-like cytokine pattern originally described by Groux et al. [59].

Mechanisms (Fig. 4)

The mechanisms of action of immune regulatory suppressor T cells have yet to be fully understood. Beside the presence of high levels of immune suppressive cytokines IL-4 and IL-10 in the microenvironment, there is increasing evidence that apoptosis may also play an important role in immunosuppression [60, 61]. Indeed, strains of mice that are genetically deficient in Fas (lpr) and/or FasL (gld) are resistant to UVB-induced immune suppression [34, 62]. In addition, we demonstrated that UVB-induced apoptotic leukocytes can nonspecifically facilitate allogeneic BM engraftment suggesting their immunosuppressive properties [63]. Schwarz et al. [64] demonstrated that suppressor T cells mediate their inhibitory property by inducing apoptosis of antigen-presenting cells. Addition of IL-12 to cocultures of UVB-induced T suppressor cells and dendritic cells significantly reduced the number of these dead cells. The authors speculated that IL-12 was able to break UVB-induced tolerance by rescuing LC from T suppressor cell-induced apoptosis. They recently demonstrated that IL-12 caused a remarkable reduction in UV-specific DNA lesions through the induction of DNA repair [65]. Another possibility is the secretion of essential immune suppressive cytokines IL-4 and IL-10 by UVB-induced apoptotic T cells [66]. Considering the low penetration of UVB in the skin, it may be unlikely that direct UVB exposure and UVB-induced DNA damage occur on T cells. It is conceivable, however, that FasL expression on DNA-damaged LC may stimulate the production of T suppressor cells which may act by inducing apoptosis in the responding effector T cells. On the other hand, FasL expression on DNA-damaged LC may directly induce apoptosis of the antigen-specific effector T cells [62].

UVB-induced immune suppressive mediators

Biological response modifiers and cytokines play an essential role in UV-induced immune suppression.

Keratinocytes

Upon UVB irradiation keratinocytes produce and secrete a large number of proinflammatory soluble factors Il-1,Il-6, IL-8, TNFα, and prostaglandin E2, which are most likely responsible for the onset of the inflammation and the induction of chemotaxis of the neutrophils and macrophages into the skin [46, 67, 68]. Most of them have also been detected in the serum of UVB-exposed human volunteers and mice. TNFα has been suggested as an important mediator in local UVB-induced immunosuppression [69]. However, UV-induced inhibition of local CHS is only partially abrogated by antibodies against TNFα [70] Furthermore, these results have been recently challenged by studies performed in TNF-receptor-deficient mice [71], suggesting that other mediators are involved. In contrast, antibodies against IL-10 block UVB-induced immune tolerance but had no effect on immune suppression of CHS whereas they are able to restore normal DTH response after UVB irradiation [72, 73]. These data have been confirmed in IL10-deficient mice [74] indicating that IL-10 is a key mediator of UVB-induced systemic immunosuppression. In murine skin, IL-10 is predominantly secreted by keratinocytes after UV exposure, whereas in human skin it is mainly produced by infiltrating CD11 + macrophages [75]. Although the interactions between these different mediators are not fully understood, recent data suggest that a cytokine cascade is activated by UVB exposure leading to systemic immune suppression. One consequence of UVB exposure is a shift in the activation of T cells from a Th1- to a Th2-type immune response [76]. The mechanism through which UVB irradiation influences the activation of T cell subsets appears to involve the alteration of antigen presenting functions of LC. Treatment of LC with UVB-induced IL-10 blocked antigen presentation to Th1 cells but did not interfere with antigen presentation to Th2 clones [72, 77]. In addition, prostaglandine E2 released by UVB-irradiated keratinocytes induces peripheral blood leukocytes to produce IL-4 which then causes the secretion of IL-10 leading to systemic suppression of antigen presenting function and induction of DTH to allogeneic cells [78]. PGE2 does appear to have an critical role in UVB-induced systemic immune suppression and UVB exposure can directly activate PGE2 synthesis in irradiated keratinocytes [79] via the induction of cyclooxygenase-2 (COX-2). Moreover, UVB-irradiated keratinocytes are able to secrete platelet activating factor (PAF), which in turn upregulates their COX-2 gene expression and PGE2 secretion [80, 81]. Walterscheid et al. [24] recently proposed the following UVB-induced cascade (Fig. 5). First, pyrimidin dimers in the DNA of irradiated keratinocytes are produced which activate phospholipase A2 through activation of MAP kinase p38. PAF is then released, binds to the PAF-receptor on adjacent keratinocytes and incites them to secrete PAF and up-regulate production of PGE2 and other immune modulatory cytokines. UVB irradiation also activates the complement cascade and the third component of the complement (C3b) in keratinocytes contributing to the induction of immune suppression and tolerance through the ligation of CD11b + infiltrating macrophages [43, 46]. In addition, neurogenic peptides secreted by keratinocytes, but also by nerve cells (calcitonin-gene related peptide: CGRP, pro-opiomelanocortin-derived peptide, and alpha-melanocyte-stimulating hormone), and nitric oxide seem to play a role in mediating UVB-induce immunosuppression. Indeed topical treatment with antagonists of the previous mediators following UVB irradiation but prior immunization with hapten was able to almost completely restore the UVB-induced suppression [82, 83].

Langerhans cells

PGE2 is a potent inhibitor of IL-12 production by peripheral blood monocytes [84]. IL-12 produced by LC and macrophages is the major cytokine in the activation of Th1 cells [85], and injection of recombinant IL-12 into mice overcomes UV-induced immune suppression, and the induction of suppressor T cells and tolerance [86, 87]. The ability of IL-12 to reverse UV-induced immune suppression was independent of its ability to up-regulate IFNγ secretion and to activate Th1 cells, but rather involves suppression of IL-10 production [88]. UVB-irradiation suppresses the secretion of IL-12p70 by LC while promoting IL-12p40 production. Suppression of IL-12p70 production coupled with induction of IL-12p40 may explain why LC fail to present antigen to Th1 clones [88].

Macrophages

In addition to being the major source of IL10 in human irradiated epidermis [75], UVB-induced infiltrating macrophages fail to secrete IL-12, thus contributing to UV-induced immune suppression and tolerance induction [42].

Neutrophils

UVB irradiation induces a strong expression of IL-4 mRNA and protein in normal human skin both in situ and in blister fluid [47]. Teunissen et al. [46] have demonstrated that CD15 + neutrophils were the source of IL-4 production and contributed to the immunosuppressive state of irradiated epidermis.

Mast cells

Mast cells are activated by PAF [89], but also by UCA and neuropeptides such as CGRP [90, 91] and may secrete immune regulatory cytokines involved in UVB-induced suppression [92]. Histamine has the capacity to induce PGE2 production by keratinocytes [93] and potently suppresses IL-12 and stimulates IL-10 production by monocytes [94].

Conclusion

In the majority of studies documenting UV-induced immune suppression, the UV was administrated to naïve animals prior to immunization in order to suppress the induction of immunity. In a recent study, Nghiem et al. [95] demonstrated that UVB activate similar immunologic pathways to suppress the elicitation of the immune response. Although the role of UVB in inducing skin cancer and immune suppression is well known, the role of UVA, which represents 95 % of the ambient UV radiation on earth, has been less widely studied. Some of the results are contradictory, but recent studies have highlighted the role of UVA in UV-induced immune suppression [6, 96-99]. Nghiem et al. [6] demonstrated that exposure to UVA II (320 to 340 nm) post immunization suppressed the elicitation of DTH to Candida albicans. Furthermore, suppression of both local and systemic DTH response to recall antigens in human volunteers was observed after sunlight irradiation, and only UVB and UVA absorbing sunscreens afforded immune protection [98]. It was also remarkable to note that UVA radiation induces similar immunological mechanisms to those observed after UVB + UVA irradiation, including the role of IL-10, the generation of antigen-specific suppressor T cells known as NKT cells, and more surprisingly the role of DNA damages as the initiating event [95]. Since the transplantation experiments conducted 30 years ago by Margaret Kripke [3], important advances in the “photoimmunology” area have been made. The evolutionary explanation of the UV-induced immune suppressive response may be to prevent the UV-altered molecules being recognized as “non-self” neoantigens. If immune responses were generated to these molecules, this might result in chronically inflamed skin, as seen in patients with polymorphous light eruption [100]. Thus the immune modulation following UV exposure may be desirable under many circumstances and may explain the efficiency of phototherapy in various T-cell mediated dermatoses [101]. On the other hand, UV-induced immune suppression might not be desirable in the case of skin cancers or infection, since development of tumoral cells or infectious agents are facilitated by escape from immune surveillance. The findings of UV-induced immune suppression should be considered as relevant to public health [5]. n

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