Transforming Growth Factor-β Signaling Guides the Differentiation of Innate Lymphoid Cells in Salivary Glands

Abstract

Summary The signals guiding differentiation of innate lymphoid cells (ILCs) within tissues are not well understood. Salivary gland (SG) ILCs as well as liver and intestinal intraepithelial ILC1 have markers that denote tissue residency and transforming growth factor–β (TGF-β) imprinting. We deleted Tgfbr2 in cells expressing the ILC and NK marker NKp46 and found that SG ILCs were reduced in number. They lost distinct tissue markers, such as CD49a, and the effector molecules TRAIL and CD73. Expression of the transcription factor Eomes, which promotes NK cell differentiation, was elevated. Conversely, Eomes deletion in NKp46+ cells enhanced TGF-β-imprinting of SG ILCs. Thus, TGF-β induces SG ILC differentiation by suppressing Eomes. TGF-β acted through a JNK-dependent, Smad4-independent pathway. Transcriptome analysis demonstrated that SG ILCs had characteristic of both NK cells and ILC1. Finally, TGF-β imprinting of SG ILCs was synchronized with SG development, highlighting the impact of tissue microenvironment on ILC development

A point mutation in the Ncr1 signal peptide impairs the development of innate lymphoid cell subsets

“…Although loss of NKp46 did not impair ILC1 numbers, we show that the apoptosis-inducing ligand TRAIL, which can be induced by TGF-β 43 and through viral binding to NKp46 44 was lacking implying that NKp46 may play a role in regulating TRAIL expression. NKp46 is also a key marker of one of the three subsets of ILC3.…”

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

“…Rroid −/− mice showed a significant reduction in liver CD49a + ILC1s as well as in T-bet + ILC1s in the lung and intraepithelial lymphocyte (IEL) compartment in the gut (Figure 1G–H). ILC1 populations have also been described in the small intestine lamina propria (SI-LPL) and salivary glands (SG) (Cortez et al, 2016; Klose et al, 2014). However, we found equivalent numbers of SI-LPL and SG ILC1s (Figure 1H), indicating that the Rroid locus is not required for the homeostasis of these unique ILC1 populations.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…Nonetheless, there may be other pathways for the differentiation of adaptive NK cells, and there may also be distinct types of adaptive NK cells, potentially within tissues. For example, as mentioned earlier, there are liver-resident adaptive NK cells in mice that are characterized by the expression of CXCR6 and that were recently shown to be reliant on expression of the aryl hydrocarbon receptor (Cortez et al, 2016; Keskin et al, 2007; O’Leary et al, 2006; Paust et al, 2010; Zhang et al, 2016). It remains to be determined if such liver-resident adaptive NK cells ultimately rely on a developmental pathway that is distinct from that of MCMV-associated adaptive NK cells, which can derive from splenic KLRG1 − cNK cells.…”

“…In light of this notion one can also envision a scenario in which trNK cells could derive via a common developmental pathway shared by cNK cells and that at some point a subset of NKDIs diverges, undergoes terminal differentiation, and ultimately takes up permanent residence within tissues as trNK cells (Figure 2). This could occur in response to extrinsic local factors such as transforming growth factor-beta (TGF-β) that has been shown to promote trNK phenotypes in human uterus and mouse salivary gland tissues (Cortez et al, 2016; Keskin et al, 2007). Alternative possibilities are that trNK cells derive through completely distinct developmental pathways, potentially starting from distinct tissue-resident HPC populations or NK cell progenitor populations that have been described (Bozzano et al, 2015; Renoux et al, 2015).…”