The Helix-Loop-Helix Protein ID2 Governs NK Cell Fate by Tuning Their Sensitivity to Interleukin-15

Abstract

The inhibitor of DNA binding 2 (Id2) is essential for natural killer (NK) cell development with its canonical role being to antagonize E-protein function and alternate lineage fate. Here we have identified a key role for Id2 in regulating interleukin-15 (IL-15) receptor signaling and homeostasis of NK cells by repressing multiple E-protein target genes including Socs3. Id2 deletion in mature NK cells was incompatible with their homeostasis due to impaired IL-15 receptor signaling and metabolic function and this could be rescued by strong IL-15 receptor stimulation or genetic ablation of Socs3. During NK cell maturation, we observed an inverse correlation between E-protein target genes and Id2. These results shift the current paradigm on the role of ID2, indicating that it is required not only to antagonize E-proteins during NK cell commitment, but constantly required to titrate E-protein activity to regulate NK cell fitness and responsiveness to IL-15.

Group 1 Innate Lymphoid Cell Lineage Identity Is Determined by a cis-Regulatory Element Marked by a Long Non-coding RNA

“…Therefore, we sought to establish whether Rroid -mediated regulation of Id2 in group 1 ILCs is required to prevent the aberrant expression of genes classically associated with adaptive lymphocytes in group 1 ILCs. Gene set enrichment analysis (GSEA) confirmed a significant enrichment of known Id2 -dependent genes in our RNA-seq dataset (Figure 4E)(Delconte et al, 2016). Furthermore, expression of T and B cell specific genes (e.g.…”

“…Transcription factor footprinting analysis revealed enrichment of binding sites for E2A and E2-2 (encoded by Tcf3 and Tcf4 , respectively) within the 2837 open chromatin peaks specific to Rroid -deficient NK cells (Figure 4G–H). Furthermore, both binding sites and expression of the E-protein target Tcf7 (Delconte et al, 2016; Masson et al., 2013) were also enriched in regions of open chromatin specific to Rroid −/− NK cells (Figure 4H and Figure S4D). Consistent with our previous finding indicating that adaptive lymphocyte genes are derepressed in the absence of the Rroid locus, open chromatin peaks in Rroid −/− NK cells were significantly associated with genes in the T and B cell receptor signaling pathways (Figure 4I).…”

“…Furthermore, IL-15 has been previously shown to induce Id2 expression in NK cells (Delconte et al, 2016). Thus, we next investigated whether the Rroid locus is required for IL-15-mediated control of Id2 in group 1 ILCs.…”

“…Moreover, tightly regulated Id2 expression maintains the lineage identity of differentiated ILCs and thus it is critical for their function (Delconte et al, 2016). Yet how Id2 expression is regulated in mature ILCs has remained largely unknown.…”

“…For example, NK cells and ILC1s are unique in that they require IL-15 for their differentiation, function and homeostasis (Klose et al, 2014). Recent evidence suggests that IL-15 regulates group 1 ILCs by promoting Id2 expression (Delconte et al., 2016). In this study, we found that STAT5 binds to specific elements within the Rroid locus in response to IL-15 stimulation in NK cells and that this locus is necessary for adequate STAT5 deposition at the Id2 promoter in ILC1s, which in turn is critical to induce Id2 expression.…”