Does the developmental status of Valpha14i NKT cells play a role in disease?

CD1d-restricted natural killer T (NKT) cells that express an invariant Valpha14 T-cell receptor (TCR) represent a subset of T cells implicated in the regulation of several immune responses, including autoimmunity, infectious diseases, and cancer. Their immunoregulatory functions are defined by their ability to rapidly and abundantly produce cytokines when activated. Unlike conventional T cells, Valpha14i NKT cells appear unique in their tendency to simultaneously produce both Th1 and Th2 cytokines, and whereas they enhance immunity in some disease models, they are reported to suppress immunity in others. This makes their effect on immune responses unpredictable. We reported recently that several important changes in gene expression occur in the course of Valpha14i NKT cell development. Immature and mature Valpha14i NKT cells differ in their expression of cytokines and chemokines, their cytotoxicity, and their expression of diverse chemokine receptors important for their migration. These results suggest that functionally distinct and developmentally linked subsets of Valpha14i NKT cells exist. Although mature NKT cells make up the majority of the peripheral NKT cells, a steady and sizable number of immature NKT cells migrate from the thymus into the periphery each day. These immature NKT cells, contrary to their name, are functional but are likely to behave quite differently from their mature counterparts. To what extent the developmental status of Valpha14i NKT cells plays a role in the outcome of any given immune response remains to be determined. Here we review the current knowledge of Valpha14i NKT cell development and propose that different developmental intermediates might be responsible for the various effects that have been observed in the many models where Valpha14i NKT cells have been implicated.