Development of invariant natural killer T cells

Abstract

Invariant natural killer T (iNKT) cells develop into functionally distinct subsets. Each subset expresses a unique combination of transcription factors that regulate cytokine gene transcription upon activation. The tissue distribution and localization within tissues also varies between subsets. Importantly, the relative abundance of the various subsets is directly responsible for altering several immunological parameters, which subsequently affect the immune response. Here, I review recent advances in our understanding of the molecular regulation of iNKT cell subset development.

Figure 1

Schematic view of mouse iNKT cell development in the thymus. The model incorporates the previously described linear differentiation model using the proposed stages as well as the newly described model of differentiated subsets. The branch point between the three subsets remains poorly defined. Cell surface phenotypes for each stage and/or associated with a given subset are indicated. Expression of transcription factors as well as the associated cytokine production after activation of a given subset is shown. Molecules, transcription factors and/or signaling pathways involved in the developmental progression are indicated. The amounts of Id3 and PLZF are inversely correlated to the amounts of Id2 and Let-7 in the three main terminally differentiated iNKT subsets. Expression of RANK-L and CD40-L on CD4+ stage 1/2 iNKT cells was shown to influence the development of Aire+ mTECs [48]. The expression of these two tumor necrosis factor family receptors was not examined by iNKT cell subsets. Secretion of IL-4 by iNKT2 cells conditions CD8T cells to become ‘memory-like’ (CD44 high, CD122+, (Eomes)odermin+) and causes dendritic cells to produce the CCL17 and CCL22 chemokines [6]. In addition to differential transcription factor expression, iNKT2 (predominantly CD4+) and iNKT17 (predominantly DN) subsets can be further differentiated by cell surface expression of CD27 [6], IL-23 receptor and CD103 integrin [9]. It remains unclear when these markers are first expressed on these subsets with regards to their developmental stages (i.e. CD44 low versus CD44 high).