Development and selection of Vα14i NKT cells

V alpha 14 invariant natural killer T (V alpha 14i NKT) cells are a unique lineage of mouse T cells that share properties with both NK cells and memory T cells. V alpha 14i NKT cells recognize CD1d-associated glycolipids via a semi-invariant T cell receptor (TCR) composed of an invariant V alpha 14-J alpha 18 chain paired preferentially with a restricted set of TCR beta chains. During development in the thymus, rare CD4(+) CD8(+) (DP) cortical thymocytes that successfully rearrange the semi-invariant TCR are directed to the V alpha 14i NKT cell lineage via interactions with CD1d-associated endogenous glycolipids expressed by other DP thymocytes. As they mature, V alpha 14i NKT lineage cells upregulate activation markers such as CD44 and subsequently express NK-related molecules such as NK1.1 and members of the Ly-49 inhibitory receptor family. The developmental program of V alpha 14i NKT cells is critically regulated by a number of signaling cues that have little or no effect on conventional T cell development, such as the Fyn/SAP/SLAM pathway, NF kappa B and T-bet transcription factors, and the cytokine IL-15. The unique developmental requirements of V alpha 14i NKT cells may represent a paradigm for other unconventional T cell subsets that are positively selected by agonist ligands expressed on hematopoietic cells.