Alternative pathway for the development of V14 NKT cells directly from CD4CD8 thymocytes that bypasses the CD4CD8 stage.

Although invariant V14 natural killer T cells (NKT cells) are thought to be generated from CD4CD8 double-positive (DP) thymocytes, the developmental origin of CD4CD8 double-negative (DN) NKT cells still remains unresolved. Here we provide definitive genetic evidence obtained, through studies of mice with DP-stage-specific ablation of expression of the gene encoding the recombinase component RAG-2 (Rag2) and by a fate-mapping approach, that supports the proposal of the existence of an alternative developmental pathway through which a fraction of DN NKT cells with strong T-helper-type-1 (T1)-biased and cytotoxic characteristics develop from late DN-stage thymocytes, bypassing the DP stage. These findings provide new insight into understanding of the development of NKT cells and propose a role for timing of expression of the invariant T cell antigen receptor in determining the functional properties of NKT cells.