The Multifunctionality of Human V?9Vd2?d T Cells: Clonal Plasticity or Distinct Subsets?

The dominant subset of ?d T cells in human peripheral blood expresses V?9 paired with Vd2 as variable TCR elements. V?9Vd2 T cells recognize pyrophosphates derived from the microbial non-mevalonate isoprenoid biosynthesis pathway at pico- to nanomolar concentrations. Structurally related pyrophosphates are generated in eukaryotic cells through the mevalonate pathway involved in protein prenylation and cholesterol synthesis. However, micromolar concentrations of endogenous pyrophosphates are required to be recognized by V?9Vd2 T cells. Such concentrations are not produced by normal cells but can accumulate upon cellular stress and transformation. Therefore, many tumour cells are susceptible to ?d T cellmediated lysis owing to the overproduction of endogenous pyrophosphates. This explains why V?9Vd2 T cells contribute to both anti-infective and anti-tumour immunity. Ex vivo analysed V?9Vd2 T cells can be subdivided on the basis of additional surface markers, including chemokine receptors and markers for naive and memory T cells. At the functional level, V?9Vd2 T cells produce a broad range of cytokines, display potent cytotoxic activity, regulate a beta T cell responses, and quite surprisingly can act as professional antigen-presenting cells. Thus, an exceptional range of effector functions has been assigned to a population of T cells, which all recognize invariant exogenous or endogenous pyrophosphates that are not seen by any other immune cell. Here, we discuss whether this plethora of effector functions reflects the plasticity of individual V?9Vd2 T cells or can be assigned to distinct subsets.