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Key Words: Fas ligand • ultraviolet radiation • immunosuppression • CD95 • T suppressor cells
Abbreviations used: CHS, contact hypersensitivity; DTH, delayed type hypersensitivity; FasL, Fas ligand; NR, nonirradiated; RT, reverse transcriptase; UVR, UV-irradiated.
Exposure to UV-B radiation from sunlight is a significant worldwide environmental hazard. UV exposure induces the most common malignancy in humans, skin cancer, with an estimated 1,000,000 cases per year in the United States (1). UV exposure also significantly downmodulates immune responses, exacerbating a number of infectious diseases and permitting the outgrowth of highly antigenic UV-induced skin tumors in mice (1, 2). The effects of UV on the immune system have been clinically exploited to attenuate pathophysiological responses associated with autoimmune disease in the skin (e.g., psoriasis), transfusion-associated graft-versus-host disease, and tumor growth (e.g., cutaneous T cell lymphoma) (3–5). Elucidating the mechanism(s) underlying UV-induced immunosuppression may permit significant advances in the therapeutic use of UV light and define a target for intervention in infectious diseases adversely affected by UV exposure. Moreover, the contribution of UV-induced immune suppression to skin carcinogenesis could be more accurately defined.
A large body of evidence supports the concept that exposure to UV radiation can suppress cellular immune responses in animals and humans to antigens applied both locally (at the site of irradiation) and distally (at a nonirradiated [NR]1 site) (6). Acute exposure to UV-B radiation alters the local site such that epicutaneous application of hapten fails to induce contact hypersensitivity (CHS) and instead induces tolerance in UV-B–susceptible mice (7, 8). Acute UV-B exposure can also result in diminished CHS and delayed type hypersensitivity (DTH) responses when antigens are applied epicutaneously or subcutaneously, respectively, at NR sites (6, 9, 10). Suppression of immune responses to antigens administered at distant, NR sites is known as systemic immune suppression and is characterized by the generation of antigen-specific splenic T suppressor cells (11– 13). Although the phenotype and mode of action of the T suppressor cell population remain largely uncharacterized, previous studies have documented that UV-induced immune suppression can be transferred to naive, NR animals by CD4+ cells from UV-irradiated (UVR), antigen-primed mice (14, 15). Suppressor cells cannot be elicited by either UVR or antigen alone but require the introduction of antigen at a critical time after irradiation (16, 17). Suppressor cell activity appears to be targeted to the Th population and requires IL-10 for both induction and function (18–20). Data from a number of laboratories suggest that one consequence of UV-B exposure is a shift from a Th1- to a Th2-type immune response, resulting in the suppression of CHS and DTH induction and the generation and maintenance of suppressor cells (19–24).
DNA damage (in the form of cyclobutane pyrimidine dimers) has been identified as the initial photobiological event triggering UV-induced systemic immune suppression to most antigens in the mouse (25, 26). Application of liposomes containing bacteriophage T4 endonuclease V (an excision repair enzyme specific for pyrimidine dimers) to UV-irradiated skin can repair the UV-induced DNA damage in the skin, diminish UV-induced Th2-type cytokine production, reverse UV-induced systemic suppression, and prevent the generation of UV-induced suppressor cells (27). Conversely, inducing DNA damage in the skin using liposomes containing HindIII can result in the production of Th2-type cytokines and the systemic suppression of CHS and DTH responses (28, 29). These observations point to DNA damage as a central mechanism underlying UV-induced immune suppression and suggest a sequence of events in which UV-initiated DNA damage triggers immunomodulatory cytokine production, the generation of CD4+ suppressor cells, and immune perturbations leading to diminished CHS and DTH responses. Considering that primary immunosuppression and the generation of suppressor cells are dissociable events and that immunomodulatory cytokine production is necessary, but not sufficient, to recapitulate the effects of UVR on the immune response, the existence of additional molecular linkages between DNA damage and immune suppression is likely.
Recent evidence has documented the interactions of Fas and Fas ligand (FasL) in the control of specific T cell–mediated immune responses (reviewed in 30). This complementary receptor–ligand pair initiates apoptosis in activated lymphocytes (31, 32) and is required for the maintenance of peripheral tolerance (33) and immune privilege (34, 35). Several lines of circumstantial evidence led us to query whether Fas/FasL interactions were involved in systemic UV-induced immune suppression. First, FasL is inducible by DNA damage (36) and is upregulated in normal skin following exposure to UV irradiation (3); second, Fas/FasL interactions have been shown to mediate antigen-specific immune suppression (35, 37); third, CD4+ T cells have been documented to upregulate FasL expression and induce autocrine, paracrine, or juxtacrine cell death (38–41); and finally, the preferential elimination of Th1 cells by FasL has been reported (42). To test the hypothesis that Fas and FasL are involved in the immunomodulatory effects of UVR, we investigated the biological consequences of Fas and FasL loss of function using lpr and gld mice, respectively, on UV-induced systemic immune suppression and the generation of transferable suppressor cells.
UV-B Radiation Source and Irradiation Procedure.
DTH Responses to Candida albicans and Alloantigen.
CHS Response to FITC.
Transfer of Spleen Cells.
Detection of FasL mRNA.
Statistical Analysis.
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Mice.
Specific pathogen-free C3H/HeJ, Balb/c, and C57Bl/6 male mice were purchased from the National Cancer Institute– Frederick Cancer Research Facility Animal Production Area. C57Bl/6 gld/gld and C57Bl/6 lpr/lpr male mice were purchased from The Jackson Laboratory. C3H/HeJ gld/gld male mice were generated from a breeder colony maintained in our facility and used between 8 and 14 wk of age. Mice were housed in a pathogen-free barrier facility accredited by the American Association for Accreditation of Laboratory Animal Care, in accordance with current U.S. Department of Agriculture, Department of Health and Human Services, and National Institutes of Health regulations and standards. All animal procedures were approved by the Institutional Animal Care and Use Committee.
A bank of six Westinghouse FS40 sunlamps was used as a source of UV radiation as described (25).
DTH responses were assessed as previously described (9). In brief, mice were shaved and exposed to UV-B radiation (2–5 and 15 kJ/m2 for C. albicans and alloantigen, respectively). 3 d later, mice were sensitized by subcutaneous injection of antigen (107 formalin-fixed C. albicans or 5 x 107 Balb/c spleen cells or cell equivalents). 6–10 d after antigen sensitization, mice were challenged by injecting either purified C. albicans protein (Allercheck, Inc.) or 107 Balb/c spleen cells in the footpad. 24 h later, footpad swelling was quantitated using a spring loaded micrometer (Swiss Precision Instruments). Specific footpad swelling (
swelling) was determined by subtracting the footpad swelling in mice that were challenged but not sensitized from that observed in mice that were sensitized and challenged. Percent suppression was calculated as: % suppression = 1 – (T – N/P – N) x 100, where N = negative control (response of unsensitized mice to challenge), P = positive control (response of sensitized mice to challenge), and T = test group (response of mice given UV irradiation before sensitization and challenge). Treatment groups consisted of 3–6 (typically 5) mice; both hind footpads were measured.
CHS responses were determined as previously described (43). In brief, for FITC responses, the abdominal hair of mice was shaved, their ears protected with electrical tape, and the animals exposed to UV-B radiation (2 kJ/m2). 3 d later, the dorsal hair was shaved and the animals sensitized by epicutaneous application of 400 µl of 0.5% FITC (Isomer I, Aldrich Chemical Co.) in acetone–dibutylphthalate (1:1, vol/vol). 5–7 d later, the mice were challenged by applying either 10 µl 0.5% FITC to the ventral and dorsal surfaces of both ears. Ear swelling (swelling) was quantitated 24 h later using a spring loaded micrometer and specific ear swelling determined by subtracting the ear swelling in mice challenged but not sensitized from that observed in mice that had been sensitized and challenged; percent suppression was calculated as described for DTH responses.
For transfer of splenic suppressor cell populations, mice were killed, spleens harvested, and single cell suspensions prepared immediately following DTH or CHS analysis. Approximately 108 spleen cells were injected into the tail veins of NR, naive recipient mice and the animals immediately sensitized by subcutaneous injection (107 formalin-fixed C. albicans or 5 x 107 Balb/c spleen cells) or epicutaneous application (400 µl 0.5% FITC). 6–10 d later, mice were challenged as described above and DTH or CHS responses determined 24 h later.
C3H/HeJ mice were shaved and exposed to 15 kJ/m2 UV radiation as described above. 3 d after UVR, mice were killed and inguinal, axillary, and brachial lymph nodes harvested. Lymph nodes were mechanically dissociated and washed, and RNA was extracted with Trizol (GIBCO BRL) per manufacturer's instructions. Reverse transcriptase (RT) and PCR reactions were performed with the GeneAmp PCR kit (Perkin-Elmer Corp.) using the following primer sequences: FasL, 5'-ATCCCTCTGGAATGGGAAGA-3' (forward), 5'-CCATATCTGTCCAGTAGTGC-3' (reverse); β actin, 5'-TCCTGTGGCATCCATGAAACT-3' (forward), 5'-CTTCGTGAACGCCACGTGCTA-3' (reverse). 35 cycles of PCR were performed: 30 s at 94°C, 45 s at 55°C, and 60 s at 72°C, using a Perkin-Elmer Gene Amp 9600.
For DTH and CHS analysis, the probability of no difference between treatment and controls was analyzed in a factorial ANOVA using Fisher's protected least significant difference test with a 5% significance level. Statistical analyses were performed with Statview software (Abacus Concepts; v4.5).
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UV-induced Systemic Immune Suppression Requires Fas/ FasL Interactions.
Normal mice exposed to a single dose of UVR before immunization at an NR site with formalin-fixed C. albicans or FITC exhibit a profound suppression of DTH or CHS response, respectively. To address the potential role of Fas/FasL interactions in UVR-induced systemic immune suppression, lpr or gld mice were evaluated for UV-induced immune suppression of CHS and DTH responses. The lpr mutation encodes an abnormal Fas gene containing an early retroviral transposon insertion that results in premature termination (44–47). Low levels of Fas expression (up to 50% of the level observed in wild-type mice) have been reported in lpr mice, demonstrating an incomplete Fas loss in these animals (46, 48). Mice harboring the gld mutation have a complete loss of biologically active FasL as a result of a point mutation in the FasL gene (49–51). The requirement for Fas/FasL interactions in UVR-induced immune suppression was first evaluated by comparing responses in wild-type C3H/HeJ (C3H) and FasL-deficient C3H/HeJ gld/gld (C3H/gld) mice. Both groups of animals were exposed to a single dose of UVR and immunized 3 d later at a distant NR site by epicutaneous application of FITC or subcutaneous injection of C. albicans (9). 6–10 d later, mice were challenged either on the pinnae or in the footpad with the sensitizing antigen to elicit CHS and DTH responses, respectively. Representative results from one such experiment are shown in Fig. 1. In wild-type C3H mice, UVR exposure potently suppressed both CHS and DTH responses compared with NR, positive control mice (76 and 82% suppression, respectively; P < 0.0001). In direct contrast, UVR-exposed C3H/gld mice exhibited no such immune suppression. Similar results were observed in C57Bl/6 (B6) and C57Bl/6 gld/gld (B6/gld) mice for DTH to C. albicans (data not shown). Thus, when FasL is nonfunctional, UVR-induced immune suppression is abrogated.
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Earlier work in our laboratory demonstrated the presence of DNA damage (cyclobutane pyrimidine dimers) in skin-derived dendritic cells up to 1 wk after a single acute exposure of UVR (27). As DNA damage can induce FasL expression, a potential mechanism for the requirement for FasL in UV-mediated suppression might be the inappropriate expression of FasL in the draining lymph nodes after UVR. To explore this possibility, the skin-draining lymph nodes from wild-type mice were removed 3 d after UVR and FasL expression determined by RT-PCR. As shown in Fig. 2, FasL mRNA was markedly induced in the lymph nodes of mice that received 15 kJ/m2 UVR but was undetectable in untreated control animals. Specificity was demonstrated using L929 murine fibroblasts and unactivated lpr/ lpr splenocytes as negative and positive controls for FasL expression, respectively (53). FasL induction in the skin-draining lymph nodes after UVR points to an interrelationship with DNA damage and suggests a potential scenario in which inappropriate FasL expression eliminates antigen- responsive T cells (54) or serves to clonally expand a suppressor cell population (55). Experiments are currently underway to test these possibilities.
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Transfer of UV-induced Suppression Does Not Require Recipient-derived FasL.
In the experimental models above, we have shown a stringent requirement for donor-derived FasL in UV-mediated transferable suppression. To discern whether FasL was also required in recipient mice, we evaluated UV-induced transferable suppression in FasL-deficient recipients. Such experiments were carried out by transferring spleen cells from wild-type mice that received UVR before immunization with C. albicans into either wild-type or FasL-deficient recipient mice (C3H or C3H/gld). Results from one such experiment are shown in Fig. 6. Consistent with our previous findings (Fig. 5), spleen cells from UVR- exposed, C. albicans–immunized C3H donor mice suppressed subsequent antigen responsiveness in naive C3H recipients (58% suppression relative to positive control mice; P < 0.0001). Similarly, UVR-exposed, C. albicans–immunized C3H donor spleen cells markedly suppressed subsequent antigen responsiveness in C3H/gld recipients (53% suppression relative to positive control mice; P < 0.0001), ruling out a requirement for recipient-derived FasL in transferable suppression induced by UVR. No suppression was observed when NR, C. albicans–immunized C3H splenocytes were transferred to either C3H or C3H/gld recipients, confirming a requirement for both UVR and antigen exposure in the generation of suppressor cell activity (16, 17).
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Our observations are important in that they identify FasL as a fundamental constituent of both primary and transferable antigen-specific suppression induced by UVR (Table I). The central role of FasL in UV-induced systemic suppression of CHS and DTH responses varies from that of Th2-like immunomodulatory cytokines and cis-urocanic acid, which are not shared conjointly in the suppression of CHS and DTH responses (19–21; Kripke, M.L., unpublished observations). For example, IL-10 appears to be essential for systemic UVR-induced suppression of DTH responses (20), whereas TNF-
is essential for CHS suppression (19, 60). The selective requirement of FasL for UVR- mediated suppression of CHS responses to FITC and DTH responses to Candida, but not alloantigen, is reminiscent of our previous finding that repair of UV-induced DNA damage could restore immune responses to FITC and Candida but not alloantigen (25–27; Kripke, M.L., unpublished observations). Taken with the recent report that DNA damage can activate the FasL promoter and upregulate FasL expression (61), our findings raise the interesting possibility that UVR-induced DNA damage and FasL are interrelated in the induction of UVR-induced immune suppression. The potent induction of FasL mRNA in skin-draining lymph nodes after UVR lends additional credence to this premise (Fig. 2).
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What then might be the requirement for FasL in the generation and activity of transferable suppressor cells? Considering the low penetrance of UVR in the skin, it appears unlikely that direct UVR exposure and UV-induced DNA damage occurs on T cells. It is conceivable, however, that DNA-damaged APC may influence the development of such T cells. In this regard, we have previously shown that DNA-damaged APC cluster with suppressor T cells in the draining lymph nodes after UVR and antigen exposure (27, 43, 63). Taken with the observation that Fas ligation can induce proliferation in some T cells (62), it is possible that FasL on DNA-damaged APC may act as a growth factor for UV-induced T suppressor cells in the context of the UVR-treated animal. Interestingly, Groux et al. (64) have recently described an IL-10 driven, antigen-specific CD4+ T cell that can potently suppress antigen-specific immune responses in vivo. Such findings suggest that UVR-induced immunoregulatory Th2 cytokines such as IL-10 (18–20) may also participate in the differentiation and maintenance of the suppressor cell population. On the other hand, FasL may be required for effector activity of the UV-induced suppressor cells, perhaps by inducing apoptosis in the responding recipient T cell population. Experiments are currently in progress to test these possibilities.
Recent studies highlight the complexity of the immunomodulatory effects of UV in vivo. Hart et al. have documented mast cell–derived histamine as a component of the UV-induced systemic immunosuppression of DTH responses to alloantigen (65). In contrast to our studies on UV-induced systemic immune suppression, Schwartz et al. have shown a nonessential role for FasL in UV-induced local immune suppression (66). The local model of UV-induced immune suppression differs markedly from the systemic model in both the route of administration (antigen is administered through the UV-irradiated site), specific cytokine involvement, and the requirement for FasL. For example, UVR-induced suppression of local responses is TNF- dependent and IL-10 independent and involves the production of cis-urocanic acid (67). In contrast, UVR-induced systemic immune suppression is independent of both TNF- and cis-urocanic acid but dependent upon IL-10 production (19, 20; Kripke, M.L., unpublished observations). Collectively, these findings emphasize mechanistic differences between UVR-mediated local and systemic suppression and suggest the existence of at least two nonoverlapping pathways in the generation of systemic UVR-induced immune suppression. One pathway requires FasL on host-derived APC and is sensitive to reversal by the repair of UV-induced DNA damage (25–27; Kripke, M.L., unpublished observations); the other requires histamine (65) and is independent of host-derived FasL. Interestingly, both pathways require FasL for the generation of transferable suppression but may differ in their requirement for FasL in the host (66).
In summary, our experiments document that Fas/FasL interactions are essential for UVR-induced systemic suppression of CHS and DTH responses to antigens presented by host-derived APC (Table I). The requirement for Fas/ FasL in UVR-induced immune suppression can be eliminated if antigen presentation bypasses the requirement for host-derived APC (intact alloantigen). Moreover, host- derived, but not recipient-derived, FasL expression is critically required for the generation and/or function of UVR-induced suppressor cells. The crucial role of FasL in both systemic primary and transferable UV-induced immune suppression suggests that the dysregulation of Fas-mediated apoptosis may ultimately underlie both processes.
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This work was supported by a grant from the Skin Cancer Foundation Research Program, University of Texas M.D. Anderson Cancer Center (to L. Owen-Schaub), American Cancer Society grant CIM-88929 (to L. Owen-Schaub), National Institutes of Health (NIH) grant CA52457 (to M.L. Kripke), and institutional core grant CA16672 from the National Cancer Institute. L.L. Hill is the recipient of an NIH postdoctoral fellowship and a Cockrell Foundation University Cancer Fighters Scientific Achievement Fellowship.
Submitted: 2 December 1998
Revised: 18 February 1999
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