Meeting Abstract

Cancer Immunity, Vol. 8 Suppl. 2, p. 2 (15 December 2008)

Molecules regulating the immunosurveillance of tissues

Adrian Hayday1*, Mike Girardi2, Bob Tigelaar2, Julie Lewis2, Martin Woodward1, Jessica Strid1 and Susannah Barbee1

1King's College School of Medicine at Guy's Hospital, London, United Kingdom

2Yale University School of Medicine, New Haven, CT, USA

*Presenting author

Abstract

Very many of the body's T cells are not conventionally MHC-peptide restricted, but often compose oligoclonal repertoires constitutively associated with tissues. It was proposed 20 years ago that these cells may respond rapidly to generic molecular markers of tissue dysregulation, and consistent with this, we have now shown that epidermal gamma delta T cells quickly respond to the upregulated expression in keratinocytes of a single stress-associated MHC-related molecule, Rae-1, and that this leads to a several downstream events including an unanticipated tissue infiltration by NKT cells. The functional orthologues of Rae-1 in humans include the MICA gene that is strongly implicated in the regulation of human responses to viral infection, inflammation, and to malignant transformation. Indeed, MICA is a highly polymorphic gene, with >50 alleles described. The finding that skin-associated T cells respond to Rae-1 upregulation suggests they may play a pivotal role in immunosurveillance, upstream of DC or other cells. Current studies aim to define the consequences of this T cell driven immunosurveillance under different circumstances.

The early activation of Rae-1 is a common characteristic of skin carcinogenesis that we have shown to be limited by the action of skin-associated gamma delta T cells, but only of the "wild type" / "canonical" repertoire. How specific repertoires of tissue-associated T cells form has long been a matter of speculation, but we recently helped identify a novel gene, Skint‐1, that is the prototypic member of a novel family of immunoglobulin (Ig)-like genes that are specifically expressed in skin and thymus epithelium. The mechanism-of-action and the regulation of the Skint genes is under investigation, with its potential to cast light on epithelial-T cell interactions. We are also studying the immunological roles of the closest sequence-homologs to Skint-1, namely the Btnl genes that also encode Ig superfamily molecules expressed by epithelial cells, but specifically in the gut rather than the skin. The gut is a key area of immunosurveillance, where we remain largely ignorant of immune interactions of epithelial cells. In sum, we wish to use animal models and biochemical and molecular techniques to better define the molecular basis and implications of epithelial-T cell cross-talk mediated by Skint, Btnl, and other related molecules. We have also commenced clinical translation of lessons learned to immunotherapy of carcinomas.

References

  1. Boyden LM, Lewis JM, Barbee SD, Bas A, Girardi M, Hayday AC, Tigelaar RE, Lifton RP. Skint1, the prototype of a newly identified immunoglobulin superfamily gene cluster, positively selects epidermal gamma delta T cells. Nat Genet 2008; 40: 656-662. [PubMed]
  2. Strid J, Roberts SJ, Filler RB, Lewis JM, Kwong BY, Schpero W, Kaplan DH, Hayday AC, Girardi M. Acute NKG2D-ligand upregulation promotes rapid reorganization of a local immune compartment with pleiotropic effects on carcinogenesis. Nat Immunol 2008; 9: 146-154. [PubMed]
  3. Dieli F, Vermijlen D, Fulfaro F, Caccamo N, Roberts A, Meraviglia S, Cicero G, Buccheri S, D'Asaro M, Gebbia N, Salerno A, Eberl M, Hayday AC. Targeting human γδ T cells with zoledronate and interleukin-2 for immunotherapy of hormone-refractory prostate cancer - a clinical trial. Cancer Res 2007; 67: 7450-7457. [PubMed]
  4. Lewis JM, Girardi M, Roberts SJ, Barbee SD, Hayday AC, Tigelaar RE. Selection of the cutaneous intraepithelial γδ T cell repertoire by a thymic stromal determinant. Nat Immunol 2006; 7: 843-850. [PubMed]