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

Summary MicroRNAs (miRNAs) can influence lineage choice or affect critical developmental checkpoints during hematopoiesis. To search for a role of the recently described p53-induced microRNA, miR-34a, in hematopoiesis, we performed gain-of-function analysis in murine bone marrow. Constitutive expression of miR-34a led to a block in B cell development at the pro-B cell to pre-B cell transition, leading to a reduction in mature B cells. This block appeared to be mediated primarily by inhibited expression of the Forkhead transcription factor, Foxp1. We demonstrated that Foxp1 was a direct target of miR-34a in a 3′-untranslated region (UTR)-dependent fashion. Knockdown of Foxp1 by siRNA recapitulated the B cell developmental phenotype induced by miR-34a, whereas co-transduction of Foxp1 lacking its 3′UTR with miR-34a rescued B cell maturation. Lastly, knockdown of miR-34a resulted in increased amounts of Foxp1 and mature B cells. These findings identify a role for miR-34a in connecting the p53 network with suppression of Foxp1, a known B cell oncogene.

Nfil3 is critical for normal development of innate lymphoid cell (ILC) progenitors. Nfil3-deficient mice have severely reduced lung and visceral adipose tissue ILC2s and gut-associated ILC3s, and compromised innate immunity to acute bacterial infection.