HIVEP3 inhibits fate decision of CD8+ invariant NKT cells after positive selection.

CD8+ iNKT cells are functionally different from other iNKT cells, and are enriched in human but not in mouse. To date, their developmental pathway and molecular basis for fate decision remain unclear. Here, we report enrichment of CD8+ iNKT cells in neonatal mice due to their rapider maturation kinetics than CD8- iNKT cells. Along developmental trajectories, CD8+ and CD8- iNKT cells separate at stage 0, following stage 0 DP iNKT cells, and differ in HIVEP3 expression. HIVEP3 is lowly expressed in stage 0 CD8+ iNKT cells and negatively controls their development, whereas it is highly expressed in stage 0 CD8- iNKT cells and positively controls their development. Despite no effect on IFN-γ, HIVEP3 inhibits granzyme B but promotes IL-4 production in CD8+ iNKT cells. Together, we reveal that, as a negative regulator for CD8+ iNKT fate decision, low expression of HIVEP3 in stage 0 CD8+ iNKT cells favors their development and Th1 biased cytokine responses as well as high cytotoxicity.