The transcription factor lymphoid enhancer factor 1 controls invariant natural killer T cell expansion and Th2-type effector differentiation.
Bottom Line: These cells acquire multiple effector fates during their thymic development that parallel those of CD4(+) T helper cells.LEF1 also directly augments expression of the effector fate-specifying transcription factor GATA3, thus promoting the development of Th2-like effector iNKT cells that produce IL-4, including those that also produce interferon-γ.Our data reveal LEF1 as a central regulator of iNKT cell number and Th2-type effector differentiation.
Affiliation: Committee on Immunology, Committee on Molecular Pathogenesis and Molecular Medicine, and Department of Pathology, The University of Chicago, Chicago, IL 60637.Show MeSH
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Mentions: The cytokine production profiles for the iNKT cell effector fates are substantially more flexible than in their CD4+ Th cell counterparts. Dual production of IL-4 and IFNγ is a hallmark of iNKT cells that has been attributed to their high expression of PLZF (Savage et al., 2008). Indeed, some PLZFhi iNKT cells produce both IFNγ and IL-4 after in vitro stimulation with PMA and ionomycin, whereas PLZFlo iNKT cells produced IFNγ exclusively (Fig. 4 A). Given that the majority of PLZFhi cells are iNKT2 cells, we anticipated that LEF1 would be required for the development of the dual IL-4 plus IFNγ–producing population. Indeed, in vitro stimulation of total iNKT cells with PMA and ionomycin revealed that a lower frequency of Lef1Δ/Δ iNKT cells produced the Th2 cytokine IL-4 and the frequency of IL-4 plus IFNγ producers was also reduced (Fig. 4, B and C). In contrast, the frequency of Lef1Δ/Δ iNKT cells producing IFNγ only was not different from control mice, and IL-17A–producing cells were increased (Fig. 4, B and C). Therefore, LEF1 was also required for the development of functional iNKT2 cells that produced IL-4 and IFNγ.
Affiliation: Committee on Immunology, Committee on Molecular Pathogenesis and Molecular Medicine, and Department of Pathology, The University of Chicago, Chicago, IL 60637.