Directing traffic on the NKT-cell highway: a key role for ThPOK

CD1d-restricted NKT cells include CD4(+) and DN subsets, with an additional CD8(+) subset that is present in humans but not in mice. The molecular regulation of CD4/CD8 expression by NKT cells, and differentiation of these NKT-cell subsets, is poorly understood. The transcription factors GATA3 and ThPOK regulate lineage commitment of conventional MHC class II-restricted CD4(+) T cells; however, their role in CD4/CD8 expression by CD1d-restricted NKT cells is less clear. A new study in this issue of the European Journal of Immunology demonstrates a key role for ThPOK in differentiation of NKT-cell subsets. This study reveals that GATA3 and ThPOK are necessary for the development of CD4(+) NKT cells. Furthermore, ThPOK-deficient mice generate an unusual population of CD8(+) NKT cells, which are absent in control mice. This study sheds new light on the underlying molecular events leading to the emergence of distinct NKT-cell subsets.