Most cancer immunologists focus their research on the population of lymphocytes that express the αβ T-cell receptor (TCR), which make up 95% of circulating T cells. Very little is known about the remaining T-cell population, a separate lineage that expresses the γδ TCR. Adrian Hayday and colleagues now report in Science that these cells, which localize to epithelia, can reduce skin cancer that is induced by several different regimens.

γδ T cells differ from their αβ cousins in that they do not express the CD4 or CD8 T-cell coreceptor molecules, and are not presented with processed antigen in the context of histocompatibility molecules. Instead, γδ T cells seem to interact directly with intact protein, as well as a variety of other types of organic molecules. Most γδ T cells, like αβ T cells, develop in the thymus. However, they migrate from the thymus into body tissues, especially epithelia, and such cells don't recirculate between blood and lymph nodes. They encounter antigens on the surface of the epithelial cells that surround them, rather than relying on the antigen-presenting cells that inhabit lymph nodes.

γδ T cells have been observed to infiltrate epithelial tumours, and human bowel carcinomas are known to express antigens that are recognized by this subset of T cells. But do these cells attack tumours in vivo? Hayday and colleagues set out to answer this question by comparing tumour development in normal mice to that of TCRδ−/− mice, which lack γδ T cells.

The authors decided to study cutaneous malignancy in these mice, because many γδ T cells reside in the skin, and tumour development can be easily observed there. Malignancy was induced by either injection of squamous-cell carcinoma cells or through application of different sets of chemical carcinogens to the skin. In all these models, the γδ-deficient mice developed a greater number of tumours than their wild-type littermates. Malignancy occurred at different frequencies in TCRδ−/− mice and those lacking αβ T cells, indicating that these different T-cell populations make distinct contributions to the regulation of tumour growth.

But what causes γδ T cells to recognize and attack tumours? Skin cells that were exposed to carcinogens and cultured squamous-cell carcinoma cells were all found to express Rae-1 — a ligand for the NKG2d receptor that is expressed by γδ T cells. Antibodies against Rae-1, NKG2d or γδ TCR prevented tumour-cell lysis that is mediated by epidermal cells in vitro, indicating that all these molecules are involved. The authors suggest that local populations of γδ T cells might be the first to respond to transformation of skin and other epithelial cells and that the actions of these cells should be considered for immunotherapy protocols.