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Stress gets under your skin

Nature Immunology volume 9, pages 119–120 (2008)Cite this article

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.

The major histocompatibility complex class I–related NKG2D ligands MICA (human) and Rae-1 (mouse) are often expressed after exposure to viruses, carcinogens or other cellular stress, and their ligation of the immunoreceptor NKG2D in turn stimulates the activation of cytotoxic lymphocytes, including natural killer cells and γδ 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 inflammation. They show that acute, keratinocyte-specific upregulation of Rae-1 induced rapid yet reversible changes in the organization of tissue-resident Vγ5Vδ1+ dendritic epidermal T cells (DETCs), which constitutively express NKG2D, and Langerhans cells, which lack NKG2D. These changes were followed by epithelial infiltration of unconventional αβ 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 activated and juxtaposed each other. Consequently, large sheets of keratinocytes no longer proximally contacted DETCs or Langerhans cells. Then, 1 or 2 days later, clusters of infiltrating NKG2D+NK1.1+CD4−CD8− αβ T cells with an effector phenotype and dendritic morphology were found associated with the previously empty keratinocyte sheets. These infiltrating αβ T cells expressed T cell receptors using Vβ2 but not Vβ7 or Vβ8 gene segments, and a substantial fraction was CD1d restricted. It remains to be determined what the function of these various αβ T cell subsets is in skin carcinogenesis, but the infiltrating unconventional αβ T cells had a phenotype resembling that of tumor-infiltrating lymphocytes 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 provides 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.

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Figure 1: Immune activation in the absence of TLR signaling.

Katie Ris-Vicari

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Authors and Affiliations

  1. Daniel M. Andrews and Mark J. Smyth are with the Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia. mark.smyth@petermac.org,

    Daniel M Andrews & Mark J Smyth

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Andrews, D., Smyth, M. Stress gets under your skin. Nat Immunol 9, 119–120 (2008). https://doi.org/10.1038/ni0208-119

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