A Critical Role for Fas Ligand in the Active Suppression of Systemic Immune Responses by Ultraviolet Radiation

Abstract

Induction of antigen-specific suppression elicited by environmental insults, such as ultraviolet (UV)-B radiation in sunlight, can inhibit an effective immune response in vivo and may contribute to the outgrowth of UV-induced skin cancer. Although UV-induced DNA damage is known to be an initiating event in the immune suppression of most antigen responses, the underlying mechanism(s) of such suppression remain undefined. In this report, we document that Fas ligand (FasL) is critical for UV-induced systemic immune suppression. Normal mice acutely exposed to UV exhibit a profound suppression of both contact hypersensitivity and delayed type hypersensitivity (DTH) reactions and the development of transferable antigen-specific suppressor cells. FasL-deficient mice exposed to UV lack both transferable suppressor cell activity and primary suppression to all antigens tested, with the exception of the DTH response to allogeneic spleen cells. Interestingly, suppression of this response is also known to occur independently of UV-induced DNA damage. Delivery of alloantigen as protein, rather than intact cells, restored the requirement for FasL in UV-induced immune suppression of this response. These results substantiate that FasL/Fas interactions are essential for systemic UV-induced suppression of immune responses that involve host antigen presentation and suggest an interrelationship between UV-induced DNA damage and FasL in this phenomenon. Collectively, our results suggest a model whereby UV-induced DNA damage disarms the immune system in a manner similar to that observed in immunologically privileged sites.

CD4+ T Cells Regulate CD8+ T Cell-Mediated Cutaneous Immune Responses by Restricting Effector T Cell Development through a Fas Ligand-Dependent Mechanism

“…First, the increased numbers of DC and hapten-specific IFN-␥-producing CD8 ϩ T cells in the lymph nodes of hapten-sensitized gld mice directly correlated with the increased and sustained CHS responses compared with wild-type mice. As previous studies of CHS in gld mice have shown (22,23), the magnitude of the CHS response was similar in both wild-type and gld mice 24 h after hapten challenge. Then CHS in wild-type mice begin to decrease, whereas the response in gld mice is increased and sustained by at least 96 h postchallenge, indicating lack of CHS regulation in these mice.…”

Termination of Antigen-Specific Immunity by CD95 Ligand (Fas Ligand) and IL-10

“…Enforced expression of FasL has been shown to protect allografts from rejection in some cases (15,16) but not others (17). In the skin, tolerance induced by UV irradiation involves Fas/FasL (11,18) and a number of skin diseases are thought to involve FasL (19). In this tissue, resident keratinocytes (20,21) and Langerhans cells are (22) capable of expressing FasL, while immigrating T cells (23) and NK cells (24) can also express this death-inducing ligand.…”

Loss of Fas-Ligand Expression in Mouse Keratinocytes during UV Carcinogenesis

“…Fas (APO-1/CD95) and its cognate ligand, play critical roles in the elimination of sunburn cells 20 and self-reactive lymphocytes, 21 the maintenance of immunological privilege, 22,23 the killing of cytotoxic effector cells, 24 and UV-induced immunosuppression. 25 In addition, loss of Fas expression has been shown to correlate with disease progression in colon cancers and melanoma. 26,27 Studies by Owen-Schaub et al 28 have demonstrated that the wildtype p53 protein can up-regulate Fas expression.…”