Transcriptional Control of the Development and Function of Vα14i NKT Cells

Abstract

The majority of T lymphocytes, sometimes referred to as as mainstream or conventional T cells, are characterized by a diverse T cell antigen receptor (TCR) repertoire. They require antigen priming in order to become memory cells capable of mounting a rapid effector response. It has become established, however, that there are several distinct T cell lineages that exhibit a memory phenotype in the absence of antigen priming, even as they differentiate in the thymus. These lymphocytes typically express a markedly restricted TCR repertoire and their rapid response kinetics has led to their being described as innate-like T cells. In addition, several of these subsets typically express surface markers commonly found on natural killer cells, which has led to the moniker natural killer T cells (NKT cells). This review will describe our current understanding of the unique ways whereby transcription factors control the development and function of an abundant and widely studied lineage of NKT cells that recognizes glycolipid antigens.

Innate-like functions of natural killer T cell subsets result from highly divergent gene programs

“…3a,b). Overall, these data were consistent with published observations showing that NK1.1 + i NKT thymocytes, which are mostly NKT1 cells, are quiescent 15–17 .…”

“…7a and Supplementary Table 12). KLF13 and KLF2 have been linked to the development of NKT2 cells in BALB/c mice and C57BL/6 mice, respectively 17 ; however, among genes encoding the KLF family of TFs, we found that only Klf10 expression was higher in NKT2 cells than in the other subsets (Fig. 7b), which suggested that KLF10 might be another, previously unknown participant in NKT2 differentiation.…”

Tissue-Specific Distribution of iNKT Cells Impacts Their Cytokine Response

“…When stimulated with the agonistic lipid α-galactosylceramide (αGalCer), they rapidly secrete high amounts of several cytokines, and there is growing interest in exploiting αGalCer as an immunological adjuvant (Carreno et al, 2014; Singh et al, 2014; Venkataswamy et al, 2014). iNKT cells also secrete cytokines at steady state and early after infection to influence the development and activation of surrounding immune cells (Engel and Kronenberg, 2014; Lee et al, 2013). Despite being essentially monospecific, iNKT cells nonetheless display substantial functional heterogeneity, with subsets producing different cytokines having distinct tissue localization preferences (Coquet et al, 2008; Doisne et al, 2009; Doisne et al, 2011; Michel et al, 2007; Terashima et al, 2008; Watarai et al, 2012).…”

The histone demethylase UTX regulates the lineage-specific epigenetic program of invariant natural killer T cells

“…After egress from the thymus, i NKT cells mostly reside in the liver and spleen to perform effector functions 11 . Although recent reports contribute to an understanding how key transcription factors establish i NKT cell identity in a stepwise process 12,13 , it is unclear how a multitude of transcription factors is orchestrated within an epigenetic framework that controls lineage-specific gene expression in i NKT cells.…”