© 2002 Nature Publishing Group 336 | MAY 2002 | VOLUME 2 www.nature.com/reviews/immunol REVIEWS existence of specific populations of γδ T cells, although the mechanisms used and the identity and molecular nature of the cells they interact with have not been deter- mined. This is primarily due to the heterogeneity of this population of lymphocytes. Here, we argue that γδ T cells cannot be considered as a single group of cells; rather, the functions they carry out differ according to the tissue distribution of the cells, the structure of their antigen receptors, the local microenvironment, and how and at what stage of the immune response they become activated. How these factors affect γδ T-cell functions during infectious and autoimmune diseases, as well as in cancer, will be discussed. Generating the γδ T-cell repertoire The potency of the immune system lies in its capacity to generate billions of different antigen receptors from multiple gene segments that are assembled by somatic recombination. This recombination joins any one of several variable (V ) gene segments with any one of sev- eral joining ( J ) segments and, in some cases, with diversity (D) gene segments, to form the variable region of each T-cell antigen receptor (TCR) chain. V–(D)–J junctional-region complexity is increased by the addition or removal of nucleotides in joining sites, which further contributes to receptor-structure diversity. The potential for γδ TCR diversity is enormous, despite a small V-gene repertoire (FIG. 1). The use of multiple γδ T cells, together with αβ T cells and B cells, represent the three lymphocyte lineages that are found in all ver- tebrate species that have been examined so far (TABLE 1). Although γδ T cells share many cell-surface proteins and effector capabilities — for example, lymphokine production and cytotoxicity — with αβ T cells, there are differences in the biological properties of these two T-cell lineages. Unlike αβ T cells, γδ T cells constitute only a small proportion (1–5%) of the lymphocytes that circulate in the blood and peripheral organs of most adult animals. γδ T cells are, however, more wide- spread within epithelial-rich tissues, such as the skin, intestine and reproductive tract, where they can com- prise up to 50% of T cells. Their development (which can be thymic dependent or independent), the absence of MHC restriction and the ability to recognize soluble protein and non-protein antigens of endogenous ori- gins also distinguishes them from αβ T cells. Because of this, the most important question — that is, concerning the biological functions of γδ T cells — has been diffi- cult to address and remains unanswered. The use of mice that are genetically engineered to be deficient in γδ T cells in experimental models of infectious and autoimmune diseases has focused attention on an immunoregulatory role for γδ T cells. Reports of possi- ble roles for γδ T cells, however, have been conflicting, even when similar experimental systems have been used. In some cases, this has been ascribed to the *School of Biochemistry and Molecular Biology, The University of Leeds, Irene Manton Research Building, Room 8.91h, Leeds, West Yorkshire LS2 9JT, UK. ‡ Division of Autoimmunity and Transplantation, The Walter and Eliza Hall Institute of Medical Research, Victoria 3050, Australia. Correspondence to S.R.C. e-mail: S.R.Carding@ leeds.ac.uk DOI: 10.1038/nri797 γδ T CELLS: FUNCTIONAL PLASTICITY AND HETEROGENEITY Simon R. Carding* and Paul J. Egan ‡ γδ T cells remain an enigma. They are capable of generating more unique antigen receptors than αβ T cells and B cells combined, yet their repertoire of antigen receptors is dominated by specific subsets that recognize a limited number of antigens. A variety of sometimes conflicting effector functions have been ascribed to them, yet their biological function(s) remains unclear. On the basis of studies of γδ T cells in infectious and autoimmune diseases, we argue that γδ T cells perform different functions according to their tissue distribution, antigen-receptor structure and local microenvironment; we also discuss how and at what stage of the immune response they become activated.