Invariant Natural Killer T Cell Subsets-More Than Just Developmental Intermediates

Abstract

Invariant natural killer T (iNKT) cells are a CD1d-restricted T cell population that can respond to lipid antigenic stimulation within minutes by secreting a wide variety of cytokines. This broad functional scope has placed iNKT cells at the frontlines of many kinds of immune responses. Although the diverse functional capacities of iNKT cells have long been acknowledged, only recently have distinct iNKT cell subsets, each with a marked functional predisposition, been appreciated. Furthermore, the subsets can frequently occupy distinct niches in different tissues and sometimes establish long-term tissue residency where they can impact homeostasis and respond quickly when they sense perturbations. In this review, we discuss the developmental origins of the iNKT cell subsets, their localization patterns, and detail what is known about how different subsets specifically influence their surroundings in conditions of steady and diseased states.

Keywords: cytokine secretion; development; homeostasis; invariant natural killer T cells; subsets.

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 T_reg 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 PLZF^hi 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-II^hi mTECs, which mediate negative selection of medullary SP thymocytes and T_reg maturation.