Metabolic Routes as Targets for Immunological Discrimination of Host and Parasite

In humans, T lymphocytes bearing a Vγ9Vδ2 antigen receptor (TCR) exhibit strong cytotoxic activity against cells infected by a wide variety of intracellular pathogens, from bacteria (4, 5, 13, 15, 17, 19, 25, 28) to complex eukaryotic parasites (1, 12). It is now well established that the involvement of human γδ T cells in antiinfectious immunity depends on their TCR-dependent activation by small, protease-resistant ligands containing critical phosphate residues (phosphoantigens). Peripheral Vγ9Vδ2 T cells are subjected to an intense postnatal amplification, most probably due to recurrent encounter with these widespread molecules. Such antigens have been isolated from the mycobacteria Plasmodium falciparum and Francisella tularensis (2, 7, 25, 33), and it is suspected that they exist in several other species (15, 18). Thus, it is clear that the phosphoantigens responsible for γδ T-cell activation are broadly distributed in living organisms. It has been shown that the γδ T-cell response is directed towards cells that contain live bacteria (14) as well as towards live parasites (34), which means that the presence of the recognized ligand depends on an active parasitical metabolism rather than on degradation by-products within the host cell. Finally, the absence of a requirement for classical major histocompatibility complex molecules in the activation of Vγ9Vδ2 T cells reveals a mode of antigen recognition totally different from that of αβ T cells, which enables a particularly rapid response.