γδ T cells, together with B cells and αβ T cells, are the three vertebrate cell types that use somatic DNA rearrangement to assemble the genes encoding their defining cell-surface receptors 1 . The use of variable (V), diversity (D) and joining (J) gene segments confers on the γδ T-cell receptor (TCR) great potential for diver- sity, and so, γδ T cells might be expected to contribute to pathogen-specific immune responses in much the same way as αβ T cells and B cells 2 . Instead, their role has remained much more enigmatic. Although there are reports of primate γδ T cells con- tributing to a protective memory response against mycobacterial infection 3 , and of TCRδ-deficient mice (which lack γδ T cells) being fatally compromised in their resistance to lung infection by the bacterium Nocardia asteroides 4 , TCRδ-deficient mice, for the most part, mount strong immunity to a wide range of pathogens 1 . Of the immunodeficiencies that have been noted (for example, after infection with Listeria 5,6 , vesic- ular stomatitis virus 7 or malaria parasites 8 ), most are confined to early time points after infection, which supports the view that γδ T cells contribute to the fast- acting innate response, mounted by cells that do not require substantial clonal expansion 9 . This would imply that large numbers of γδ T cells share the capac- ity to respond to the same set of antigens, rather than showing the fine antigen specificity that is characteristic of αβ T cells. Consistent with this, human γδ T cells make appar- ently polyclonal responses to low-molecular-mass pathogen-derived moieties, such as isoprenylpyrophos- phates 10 and unusual nucleotide derivatives 11 , and/or to autologous proteins that are upregulated by infected, transformed or otherwise dysregulated host cells 12 . Mouse γδ T cells respond to the MHC class-I-related proteins T10/T22 (which are known generically as thy- mus leukaemia, TL, antigens), the expression of which can be upregulated by activated cells. Direct binding of soluble recombinant T22 to a mouse γδ TCR was shown by surface plasmon resonance, and 0.4% of mouse γδ T cells in the spleen and in the gut-associated lymphoid tissue (GALT) could be detected using recombinant T22 that had been tetramerized to increase avidity 13 . The available data on T22-reactive γδ T cells, and on those that react to the related molecule T3, indicate that mouse γδ T-cell responses are also polyclonal 13,14 . The human and mouse genomes contain many genes, such as those encoding TL antigens, known as class IB MHC genes, and it has been proposed that the expression of many of these genes acts as a generic bea- con of cell dysregulation that is recognized by γδ T cells in the vicinity 15,16 . In support of this, a large number of human gut-associated γδ T cells are activated by MHC class I polypeptide-related sequence A (MICA) — a human class IB MHC protein that is expressed by stressed epithelial cells 17 — although the precise role of IMMUNOREGULATION IN THE TISSUES BY γδ T CELLS Adrian Hayday* and Robert Tigelaar ‡ For a T-cell subset to be classified as immunoregulatory, it might reasonably be predicted that in its absence, animals would experience pathological immune dysregulation. Moreover, reconstitution of the subset should restore normal immune regulation. So far, these criteria have been satisfied by only a few of the candidate regulatory T-cell subsets, but among them is the intraepithelial γδ T-cell receptor (TCR) + subset of mouse skin. In this article, we look at immunoregulatory γδ T cells, and the growing evidence for tissue-associated immunoregulation mediated by both γδ T cells and αβ T cells. NATURE REVIEWS | IMMUNOLOGY VOLUME 3 | MARCH 2003 | 233 *Peter Gorer Department of Immunobiology, Guy’s, King’s and StThomas’ Medical School, King’s College, London SE1 9RT, UK. ‡ Department of Dermatology, Yale University School of Medicine, New Haven, Connecticut 06511, USA. Correspondence to A.H. e-mail: adrian.hayday @kcl.ac.uk doi:10.1038/nri1030 REVIEWS REGULATORY LYMPHOCYTES