The immunologic revolution: photoimmunology

Abstract

UV radiation targets the skin and is a primary cause of skin cancer (both melanoma and nonmelanoma skin cancer). Exposure to UV radiation also suppresses the immune response, and UV-induced immune suppression is a major risk factor for skin cancer induction. The efforts of dermatologists and cancer biologists to understand how UV radiation exposure suppresses the immune response and contributes to skin cancer induction led to the development of the subdiscipline we call photoimmunology. Advances in photoimmunology have generally paralleled advances in immunology. However, there are a number of examples in which investigations into the mechanisms underlying UV-induced immune suppression reshaped our understanding of basic immunological concepts. Unconventional immune regulatory roles for Langerhans cells, mast cells, and natural killer T (NKT) cells, as well as the immune-suppressive function of lipid mediators of inflammation and alarmins, are just some examples of how advances in immunodermatology have altered our understanding of basic immunology. In this anniversary issue celebrating 75 years of cutaneous science, we provide examples of how concepts that grew out of efforts by immunologists and dermatologists to understand immune regulation by UV radiation affected immunology in general.

Figure 1. Cutaneous Photoimmunological Events

A number of early/immediate immune modulating events (middle panel) occur in the skin following exposure to UV including: (A) isomerization of trans-urocanic acid (UCA) to the immune suppressive cis-UCA isoform (De Fabo and Noonan, 1983; Gibbs et al., 2008), (B) production of the biologically active lipid mediator, PAF (Alappatt et al., 2000; Travers et al., 2010) which contributes to skin cancer development (Sreevidya et al., 2008) by suppressing both adaptive immunity (Walterscheid et al., 2002) and DNA repair (Sreevidya et al., 2010), and (C) recruitment of immune modulating mast cells into the dermis peaking at 6h post UV (Byrne et al., 2008). These early events precipitate a number of later photoimmunological events (bottom panel) including: (D) The production of immune modulating IL-33 in keratinocytes and dermal fibroblasts (Byrne et al., 2011), (E) the migration of epidermal Langerhan’s Cells (Streilein et al., 1980), dermal dendritic cells (dDC) (Fukunaga et al., 2010) and (F) CXCR4+ dermal mast cells to the local draining lymph nodes (DLN) (Byrne et al., 2008) (G) Activation of complement components in the skin (including those associated with the alternative pathway; Factor B and Properdin (Stapelberg et al., 2009) also contributes to UV-induced immune suppression (Hammerberg et al., 1998; Yoshida et al., 1998).

Figure 2. Photoimmunological Events Occurring in Skin Draining Lymph Nodes

Immunosuppressive signals generated in the skin are transmitted by Langerhans Cells (LC) and mast cells to the local skin-draining lymph nodes to regulate both humoral and cell-mediated immune responses. (A: left hand panel) In response to immunization with protein antigens, B are activated by IL-21-expressing T follicular helper (Tfh) cells in germinal centers to produce IgG₁ antibodies. (A: right hand panel) Mast cells that have migrated from UV-irradiated skin suppress this humoral arm of adaptive immunity by homing to B cell areas and producing IL-10 (Chacon-Salinas et al., 2011). At the same time, (B) CD207 (Langerin)+CD1d+ epidermal Langerhan’s Cells (LC) migrate from UV irradiated skin to the T cell zones where they activate IL-4-producing immunosuppressive NK-T cells (Fukunaga et al., 2010). Meanwhile, (C) UV-induced upregulation of CXCL12 (SDF1α) in B cell follicles attracts CXCR4+ dermal mast cells to the draining lymph nodes (Byrne et al., 2008). It is at this time that IL-10 producing UV-activated B regulatory cells, or “UV-B-regs” are induced (Byrne and Halliday, 2005) via a PAF and serotonin dependent mechanism (Matsumura et al., 2006).