Vδ2neg γ δ T Cells, a Multi-Reactive Tissue Subset: from Innate to Adaptive Altered-Self Surveillance

T cells are usually considered to contribute to fast-acting local immune responses. Their somewhat limited T cell receptor (TCR) diversity implies that large subsets of T cells share the capacity to respond to the same restricted set of antigens, rather than showing the fine specificity toward extremely diverse antigens, as is characteristic of T cells. This has been well demonstrated for V 9V 2 T cells, particularly in non-human primate models. However, much less is known about the other subsets of T cells, herein collectively called V 2 neg T cells. Most of these cells express the V 1 chain, some express the V 3 chain, and very few express the four remaining V chains (V 4 to V 8). All these V chains can be associated with any of the six V chains (V 2, 3, 4, 5, 8, 9). V 2 neg T cells are mainly located in epithelial tissues and the spleen, and are barely found in the circulation in normal physiological conditions. This tissue localization has limited their analysis. Establishment of murine models is difficult since murine and human T cell populations vary greatly. For example, the equivalent of murine dendritic epithelial T cells (DETC) does not exist in humans, and conversely, the equivalent of human V 9V 2 T cells is present only in primates. Therefore, human V 2 neg T cells have mostly been examined during pathological situations where their circulating levels are increased. Like V 9V 2 T cells, V 1 and V 3 T cells have been shown to be involved in widely diverse pathological contexts, such as infection, cancer, auto-immunity, and inflammation. This suggests that T cells respond to a variety of altered microenvironments induced by these situations. It is acknowledged that T cells can recognize ubiquitous stress-induced conserved antigens in their native form, and altered-self or foreign ligands presented on non-polymorphic molecules in total independence of classical MHC molecules. Since V 2 neg T cells can recognize broadly distributed antigens and are localized at the interface with the outer environment within epithelial tissues, V 2 neg T cells can act as a first line of defense in the surveillance of body integrity and microorganism infections. Nevertheless, V 2 neg T cells can also display effector/memory phenotypes similar to conventional MHC-restricted T cells. This suggests an ability to mount long-lasting anamnestic immunity similar to conventional T cells. Here, we will review what is currently known about V 2 neg T cells highlighting the pathological situations where they expand. We will also discuss what is known concerning the cellular and molecular mechanisms of their activation and their effector functions.