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: Our data demonstrated that LEF1 played an important role in the development of all iNKT cells. However, when compared with control thymic iNKT cells, there was a decreased frequency of ST1 and ST2 cells and an increased frequency of ST3 cells among the remaining Lef1Δ/Δ thymic iNKT cells (Fig. 3, A and B), despite the fact that the all iNKT cell populations were decreased in number (Fig. 3 C). Recent studies have shown that ST3 iNKT cells are largely synonymous with TBET+ iNKT1 cells, whereas ST2 cells are a mixture of RORγt+ iNKT17 cells and GATA3hi iNKT2 cells, which are also found among ST1 cells. The signature iNKT cell transcription factor PLZF is also differentially expressed among iNKT cell subsets, with the highest expression in iNKT2 cells (Lee et al., 2013). To determine how LEF1 deficiency affected iNKT cell effector subsets, we examined Lef1Δ/Δ iNKT cells for expression of PLZF and RORγt, which can be used to resolve iNKT1 (PLZFloRORγt−), iNKT2 (PLZFhiRORγt−), and iNKT17 (PLZFintRORγthi) cells (Fig. 3 D). By this definition, the frequency of iNKT1 and iNKT17 cells was increased slightly, whereas iNKT2 cells were decreased among Lef1Δ/Δ iNKT cells as compared with controls (Fig. 3, D and E), although, as expected, the absolute number of all iNKT effector subsets was reduced. (Fig. 3 F). Total iNKT cell numbers were also reduced in the liver and spleen of Lef1Δ/Δ mice as compared with control mice (Fig. 1 H); however, in these tissues the frequency of iNKT2 cells was reduced relative to that of iNKT1 cells (Fig. 3, G and H). Collectively, our data indicated that after the expansion of iNKT cells, LEF1 promoted the development of iNKT2 cells.
Affiliation: Committee on Immunology, Committee on Molecular Pathogenesis and Molecular Medicine, and Department of Pathology, The University of Chicago, Chicago, IL 60637.