Stress gets under your skin

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  • Conserved stress-inducible proteins, includ-ing members of the NKG2D ligand family, are important in immune-mediated host pro-tection from cancer and pathogen challenge. However, the prevailing model of immune cell activation is based on the ability to detect dan-ger signals1. In this model, the discrimination between dangerous and harmless depends heavily on cell death. Necrotic cells release stress protein-peptide complexes into the extracellular environment, whereas apoptotic cells are com-paratively stress free. Thus, necrosis induces immune cell activation through the release of danger signals, including Toll-like receptor (TLR) ligands, whereas apoptosis effectively prevents aberrant immunity. Of considerable interest to immunologists is the issue of whether NKG2D ligands alone are sufficient to initiate immune surveillance and/or inflammation by acting as primary activators of an immune com-partment. In this issue of Nature Immunology, Strid et al. present an elegant inducible trans-genic mouse model that demonstrates that NKG2D ligand upregulation alone substantially modulates the cellular microenvironment of the skin and directs the ensuing immune response2. Their data refute the hypothesis that de novo activation of lymphocytes requires cell necrosis and/or stimulation of microbial sensors, such as TLRs, on antigen-presenting cells (Fig. 1a,b). Coupled with that important finding is the per-haps more notable observation that the absence of Langerhans cells, the prototypic specialized antigen-presenting cells of the skin, actually sup-pressed skin carcinogenesis.

    The major histocompatibility complex class I related NKG2D ligands MICA (human) and Rae-1 (mouse) are often expressed after expo-sure to viruses, carcinogens or other cellular stress, and their ligation of the immunorecep-tor NKG2D in turn stimulates the activation of cytotoxic lymphocytes, including natural killer cells and T cells3. NKG2D signaling is linked to

    tumor immune surveillance4,5, but its intrinsic ability to acutely regulate tissue-associated immune compartments has not been examined. Strid et al. have used a simple transgenic mouse model that separates Rae-1 expression from any other aspect of tumorigenesis or inflam-mation. They show that acute, keratinocyte- specific upregulation of Rae-1 induced rapid yet reversible changes in the organization of tissue-resident V5V1

    + dendritic epidermal T cells (DETCs), which constitutively express NKG2D, and Langerhans cells, which lack NKG2D. These changes were followed by epithelial infiltrat-ion of unconventional T cells, including CD1d-restricted natural killer T cells. Within 3 days of the induction of Rae-1 expression, the typical interdigitating network of Langerhans cells and DETCs was disrupted, as DETCs and Langerhans cells became rounded and acti-vated and juxtaposed each other. Consequently, large sheets of keratinocytes no longer proxi-mally contacted DETCs or Langerhans cells. Then, 1 or 2 days later, clusters of infiltrating NKG2D+NK1.1+CD4CD8 T cells with an effector phenotype and dendritic morphology were found associated with the previously empty keratinocyte sheets. These infiltrating T cells expressed T cell receptors using V2 but not V7 or V8 gene segments, and a substantial fraction was CD1d restricted. It remains to be determined what the function of these various T cell sub-sets is in skin carcinogenesis, but the infiltrat-ing unconventional T cells had a phenotype resembling that of tumor-infiltrating lympho-cytes found in skin carcinomas. In contrast, no natural killer cells were found infiltrating the epidermis. Despite complete reconfiguration of the epidermal network, all changes were fully reversible within a few days of cessation of Rae-1 expression. Thus, this transgenic mouse pro-vides a new system with which to assess how the early events in tissue immunosurveillance may unfold. Unfortunately, the authors have not yet examined whether Langerhans cells are capable of migrating to the draining lymph node and promoting adaptive immunity after Rae-1 upregulation.

    Published work indicates that Rae-1 induc-tion occurs within hours of DNA damage6 and that NKG2D ligands are likewise upregulated in

    both humans and mice during virus infection, in transplant scenarios and in many nonmalignant inflammatory lesions (such as type I diabetes in the nonobese diabetic mouse and rheumatoid arthritis in humans)7. Transcription of the gene encoding Rae-1 is upregulated in the skin of mice within 24 hours of carcinogen treatment, and this expression is sustained throughout pap-illoma and carcinoma formation8. In addition, mice lacking T cells are highly susceptible to many regimens of cutaneous carcinogenesis, and in vitro, skin-associated NKG2D+ T cells kill skin carcinoma cells by a mechanism sensitive to NKG2D blockade. However, constitutive Rae-1 transgene expression in normal epithelium elicits local and systemic NKG2D downregula-tion and generalized but reversible defects in natural killer cellmediated cytotoxicity5. The extent of NKG2D downregulation correlates with the incidence and progression of cutane-ous carcinogenesis, emphasizing the utility of NKG2D as a marker of tumor resistance. Here, Strid et al. substantially extend those initial reports to definitively demonstrate for the first time a nonredundant function specifically for V5

    + and V1+ T cell subsets in skin immune

    surveillance and protection from skin carci-nogenesis induced by DMBA (7,12-dimethylbenz[a]anthracene) and TPA (12-O-tetradec-anoylphorbol-13-acetate). The function of T cells in tumor immunosurveillance has been puzzling, with both protective and detrimental contributions being reported in different sys-tems9; now that a complex T cell infiltrate has been detected, the contribution of various T cell subsets to host protection against papilloma formation and progression will need to be delineated. Over the past decade, a framework of cancer immunoediting has been proposed10, built on strong experimental evidence supporting the idea of three distinct phases: tumor elimination, tumor equilibrium and tumor escape. Although the ongoing battle between the immune system and cancer has been demonstrated before11, notably, Strid et al. now show that the immune system can even detect the very early signs of cellular stress that precede tumorigenesis.

    The coordinated responses to local Rae-1 can be considered a model for the early phase

    Stress gets under your skinDaniel M Andrews & Mark J Smyth

    The prevailing paradigms ascribe the initiation of immune surveillance to the detection of foreign or inflammatory danger signals. However, new work indicates that immune cells can detect early signs of cellular dysregulation that precede tumorigenesis, even in the absence of non-self signals and/or inflammation.

    Daniel M. Andrews and Mark J. Smyth are with the Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. e-mail:


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  • of tumor immune surveillance, as Rae-1 protein is upregulated rapidly during chemical carcino-genesis in areas where tumors typically develop (Fig. 1c). However, the real issue is whether treat-ment with DMBA and TPA induces NKG2D ligands in the same way that Rae-1 is acutely induced in this transgenic mouse model. DMBA and TPA trigger many local changes, including, most obviously, DNA damage and some amount of keratinocyte mutation. It will now be impor-tant to carefully monitor skin compartment changes in mice receiving repeated treatments with carcinogens.

    Also notable, given the great interest in inflammation-induced cancer, is determining whether a pivotal balance exists between an acute activation response to Rae-1 and gener-alized immunosuppression of NKG2D+ cells caused by chronic Rae-1 expression. Future investigations must evaluate whether a par-ticular NKG2D ligand expression density, for-mat (such as soluble versus membrane-bound, binding NKG2D with different affinities) and/or duration modulates the risk that inflammation will progress to cancer.

    In the context of cutaneous malignancy, per-haps the most unexpected finding of this paper is that mice specifically lacking Langerhans cells are resistant to tumor formation (Fig. 1c). Indeed, when skin is exposed to carcinogenic doses of ultraviolet B irradiation, chemical car-cinogens or tumor-promoting agents, there is a substantial reduction in Langerhans cell density. It was thought that depletion of Langerhans cells was a key event associated with the pathogenesis of skin cancer, and studies have indeed shown that agents that reduce Langerhans cell num-

    bers may also contribute to tumor promotion12. Much attention has been paid to the fact that stromal immune cells, including macrophages, may in fact promote tumor growth rather than inhibiting it. Those results notwithstanding, the initial responses of local, tissue-associated immune cells to acute activating signals are generally assumed to be protective. In part, this assumption is due to the widely accepted hypothesis that during infection and tumor growth, tissue-resident dendritic cells, including Langerhans cells, may promote the expansion of host-protective antigen-specific T cell popu-lations after their prior migration to draining lymph nodes. Evidence suggests, however, that in some immune responses Langerhans cells are dispensable for T cell activation13. Tumor-pro-moting agents such as TPA are also proinflam-matory agents, and their mechanism of action in epithelial carcinogenesis has been linked to the release of interleukin 1 and the induction of chronic inflammation in skin. It is also known that tumor necrosis factor promotes papilloma formation in the DMBA plus TPA model14, and mice deficient in the adaptor molecule MyD88 have been shown to be highly resistant to carci-nogenesis in this model15. Thus, we might ask if Langerhans cells transmit a critical MyD88-dependent signal that enhances cancer initiation. Alternatively, Langerhans cells might negatively regulate the infiltration of effector immune cells into the skin.

    Research has increased the hope that cellu-lar immune responses may be manipulated to combat cancer and that a better understanding of different immune cell activities that variably inhibit or promote tumor development will

    allow more effective clinical manipulation of cutaneous malignancy. Adjuvants for T cells are now being used clinically as part of tumor immunotherapy regimens, and it is known that human V9

    +V2+ T cells may also be directly

    activated by NKG2D. Immune regulation of the skin is complex. Resident dendritic cells have different capacities to prime T cell responses, and migration of lymphocytes into the skin is highly coordinated. The results presented here by Strid et al. provide a framework for future studies in which the interactions between skin-resident dendritic cells and DETCs and infiltrating T cells can be mapped at the molecular level. Understanding these interac-tions will have a substantial effect on the design of therapies aimed at controlling cutaneous malignancies.

    1. Matzinger, P. Annu. Rev. Immunol. 12, 9911045 (1994).

    2. Strid, J. et al. Nat. Immunol. 9, 146154 (2008). 3. Raulet, D.H. Nat. Rev. Immunol. 3, 781790

    (2003).4. Smyth, M.J. et al. J. Exp. Med. 202, 583588

    (2005).5. Oppenheim, D.E. et al. Nat. Immunol. 6, 928937

    (2005).6. Gasser, S., Orsulic, S., Brown, E.J. & Raulet, D.H.

    Nature 436, 11861190 (2005).7. Gasser, S. & Raulet, D. Semin. Cancer Biol. 16, 344347

    (2006).8. Girardi, M. et al. Science 294, 605609 (2001).9. Girardi, M. et al. J. Exp. Med. 198, 747755 (2003).10. Dunn, G.P., Old, L.J. & Schreiber, R.D. Annu. Rev.

    Immunol. 22, 329360 (2004).11. Koebel, C.M. et al. Nature 450, 903907 (2007). 12. Qu, M., Muller, H.K. & Woods, G.M. Carcinogenesis 18,

    12771279 (1997).13. Stoecklinger, A. et al. J. Immunol. 179, 886893

    (2007).14. Moore, R.J. et al. Nat. Med. 5, 828831 (1999).15. Swann, J.B. et al. Proc. Natl. Acad. Sci. (in the


    Figure 1 Immune activation in the absence of TLR signaling. (a) The paradigm of immune activation in the skin. TLR signals such as those delivered by commensal flora or CpG DNA activate skin-resident DCs to migrate to the draining lymph node, where they activate the immune response. IL, interleukin; TNF, tumor necrosis factor. (b) TLR-independent signaling and immune activation in the skin. Enforced acute expression of Rae-1 in the skin results in the activation of epidermal Langerhans cells and DETCs. The T cell populations contain a natural killer T (NKT) cell infiltrate and fill the plane of keratinocytes after initial activation of DETCs and Langerhans cells. Still unknown is whether Langerhans cells then migrate to the draining lymph node to regulate immunity. (c) Carcinogenesis induced by DMBA and TPA is controlled by the actions of DETCs and Langerhans cells. Skin-resident T cells are required for the suppression of carcinogenesis induced by DMBA and TPA. The function of T cell subsets, including natural killer T cells, recruited into the skin during treatment with DMBA and TPA requires further elucidation. In contrast, specific ablation of Langerhans cells results in the prevention of carcinogenesis induced by DMBA and TPA.






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