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. 2018 Jun 20;9:1393. doi: 10.3389/fimmu.2018.01393

Figure 1.

Figure 1

Schematic describing invariant natural killer T (iNKT) cell development and function in the thymus. Thymus-settling progenitors emigrate from the bone marrow and then mature into early thymic progenitors and progressively commit to the T cell lineage by maturing from the double negative 2 cell stage to DN3, DN4, and eventually to the double-positive (DP) cell stage. Here, they begin to rearrange their TCRα loci and can then be selected by MHC-I- and MHC-II-expressing cortical thymic epithelial cells (cTECs). Cells that successfully undergo positive selection by cTECs can become immature CD8+, CD4+, and Treg cells. By contrast, a small proportion of DP cells rearranges its TCRα locus to generate the iNKTα chain and is selected by other DP cells expressing CD1d and signaling lymphocytic activated molecules family receptors. Intracellular calcium levels are high in these post-selected stage 0 cells, which leads to NFAT translocation into the nucleus and upregulation of Egr2 and CD69. An alternative pathway (depicted by a dashed arrow) wherein a small number of DN4 thymocytes rearrange their TCRα loci to generate the iNKTα chain that can then give rise to stage 0 iNKT cells upon positive selection has also been described. These cells then transition through an uncommitted PLZFhi stage before diverging into the functionally distinct iNKT2, iNKT17, and iNKT1 subsets defined by the transcription factors GATA-3, RORγt, and T-bet, respectively. iNKT2 cells migrate from the cortex to the medulla where they begin to produce IL-4 at steady-state. This IL-4 production (as designated by red arrows) has been linked to conditioning surrounding CD8+ T cells to become innate-memory CD8+ T cells, promoting certain dendritic cell populations to secrete the chemokines CCL17 and CCL22, preventing ETP commitment to the T cell lineage and inhibiting thymic export of single positive (SP) thymocytes into peripheral tissues. RANKL expressed by medullary iNKT2 (and iNKT17) cells also promotes maturation of medullary thymic epithelial cells (mTECs) into Aire+ MHC-IIhi mTECs, which mediate negative selection of medullary SP thymocytes and Treg maturation.