Abstract
During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. Here, we show that T cell antigen receptor (TCR) signal strength governs the development of iNKT cell subsets, with strong signaling promoting iNKT2 and iNKT17 development. Altering TCR diversity or signaling diminishes iNKT2 and iNKT17 cell subset development in a cell-intrinsic manner. Decreased TCR signaling affects the persistence of Egr2 expression and the upregulation of PLZF. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2-specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. These data suggest that variable TCR signaling modulates regulatory element activity at NFAT and Egr binding sites exerting a determinative influence on the dynamics of gene enhancer accessibility and the developmental fate of iNKT cells.
Highlights
During development in the thymus, invariant natural killer T cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17
Not all gates contain the same number of cells, displaying the proportion of each iNKT cell subsets in the 30 gates revealed a direct correlation between the overall avidity of the T cell antigen receptor (TCR)–PBS57–CD1d interaction and the three major iNKT cell subset phenotypes (Fig. 1b). iNKT1 cells express the lowest amount of TCR and are stained by the tetramer with the lowest intensity. iNKT17 cells express intermediate levels of TCR
INKT2 cells express the highest TCR levels and stained more brightly with the PBS57–CD1d tetramer. This correlation is not observed with another marker of mature iNKT cells (CD44). These results demonstrate that the different thymic iNKT cell subsets have disparate but overlapping avidities for the PBS57–CD1d complex
Summary
During development in the thymus, invariant natural killer T (iNKT) cells commit to one of three major functionally different subsets, iNKT1, iNKT2, and iNKT17. By genome-wide comparison of chromatin accessibility, we identify a subset of iNKT2specific regulatory elements containing NFAT and Egr binding motifs that is less accessible in iNKT2 cells that develop from reduced TCR signaling. INKT cells recognize lipid antigens presented by CD1d, a nonpolymorphic major histocompatibility complex (MHC) class I-like antigen-presenting molecule[1]. These cells use a semiinvariant TCR made up mostly of a single invariant TCRα chain (Vα14-Jα18 in mice, Vα24-Jα18 in humans) with certain TCRβ chains (Vβ8.2, Vβ7, or Vβ2 in mice, Vβ11 in humans) to engage.
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