Murine fetal natural killer cells are functionally and structurally distinct from adult natural killer cells

132

109

During embryogenesis, the Peyer’s patch anlagen are induced by a cell population that produces lymphotoxin (LT) α1β2 following stimulation of IL-7Rα. In this study, we show that the LT-producing cell is localized within the IL-7Rα+ and integrin α4β7 (α4β7)+ population in the embryonic intestine. Lineage commitment to the LT producer phenotype in the fetal liver coincides with expression of α4β7. Before expression of α4β7, the potential of IL-7Rα+ population to generate B cells is lost. However, the progenitors for T cells and LT producer cells reside in the IL-7Rα+α4β7+ cells, but during subsequent differentiation, the potential to give rise to T cells is lost. This IL-7Rα+α4β7+ population migrates to the intestine, where it induces the Peyer’s patch anlagen. When stimulated with IL-15 or IL-3 and TNF, the intestinal IL-7Rα+α4β7+ population can differentiate into fully competent NK1.1+ NK cells or CD11c+ APCs. Expression of α4β7 is lost during differentiation of both lineages; IL-7Rα expression is lost during NK1.1+ cells differentiation. A newly discovered lineage−IL-7Rα+c-Kit+α4β7+ population in the fetal liver is committed to T, NK, dendritic, and fetal intestinal LT producer lineage, the latter being an intermediate stage during differentiation of NK and dendritic cells.

“…9). This is consistent with recent reports demonstrating a difference between adult and fetal NK cells in the ability to express Ly-49 family molecules (14,46,47). …”

Section: Fate Of Filyp Cells In Ontogenysupporting

confidence: 93%

Expression of α4β7 Integrin Defines a Distinct Pathway of Lymphoid Progenitors Committed to T Cells, Fetal Intestinal Lymphotoxin Producer, NK, and Dendritic Cells

Yoshida

Kawamoto

Santee

et al. 2001

132

109

“…Primary fetal NK cells from B6 mice do not express any Ly49 genes except Ly49e (30,31). IL-2-dependent expansion of fetal day 17 (FD17) splenic and thymic NK cells also does not lead to expression of Ly49A (31).…”

Section: Nk Cellsmentioning

confidence: 99%

Evidence for Epigenetic Maintenance of Ly49a Monoallelic Gene Expression

Rouhi

Gagnier

Takei

et al. 2006

Although structurally unrelated, the human killer cell Ig-like (KIR) genes and the rodent lectin-like Ly49 genes serve similar functional roles in NK cells. Moreover, both gene families display variegated, monoallelic expression patterns established at the transcriptional level. DNA methylation has been shown to play an important role in maintenance of expression patterns of KIR genes, which have CpG island promoters. The potential role of DNA methylation in expression of Ly49 genes, which have CpG-poor promoters, is unknown. In this study, we show that hypomethylation of the region encompassing the Pro-2 promoter of Ly49a and Ly49c in primary C57BL/6 NK cells correlates with expression of the gene. Using C57BL/6 × BALB/c F1 hybrid mice, we demonstrate that the expressed allele of Ly49a is hypomethylated while the nonexpressed allele is heavily methylated, indicating a role for epigenetics in maintaining monoallelic Ly49 gene expression. Furthermore, the Ly49a Pro-2 region is heavily methylated in fetal NK cells but variably methylated in nonlymphoid tissues. Finally, in apparent contrast to the KIR genes, we show that DNA methylation and the histone acetylation state of the Pro-2 region are strictly linked with Ly49a expression status.

“…Despite the data collected on their function, relatively little is known about how the expression of these genes is regulated. Previous studies have shown that nearly all fetal mouse NK cells express CD94/NKG2 on their surface (18) before there is any detectable expression of the Ly-49 genes, with the exception of Ly-49e (19,20). This high frequency of expression decreases after birth, when Ly-49 expression begins to approach adult levels (21,22), and so it appears that there is a developmental switch between the predominate receptors expressed by mouse NK cells.…”

mentioning

confidence: 96%

Transcriptional Control of MurineCD94Gene: Differential Usage of Dual Promoters by Lymphoid Cell Types

Wilhelm

Landry

Takei

et al. 2003

The CD94 gene product is involved in controlling NK cell activation, and is one of a family of immune receptors that is found in the NK gene complex in both humans and mice, adjacent to members of the NKG2 family. CD94 forms a heterodimeric complex with several members of the NKG2 family on the surface of NK, T, and NKT cells. These complexes recognize the nonclassical MHC class I molecules HLA-E and Qa-1b in humans and mice, respectively. The mechanism for cell type-specific expression of CD94 and other genes from the NK gene complex has not yet been elucidated. In the current study, we show that the murine CD94 gene has two promoters, one of which is upstream of a previously unidentified exon. We illustrate by quantitative real-time PCR that lymphoid cell types use these two promoters differentially and that the promoter usage seen in adult cells is already established during fetal development. We determined that the differential promoter usage by NK cells appears to be susceptible to perturbation, as both the murine NK cell line LNK, as well as cultured C57BL/6 NK cells showed altered promoter usage relative to fresh NK cells. Furthermore, the promoter activity observed in transfection assays did not correlate with expression of the endogenous CD94 gene, suggesting the involvement of chromatin structure/methylation in transcriptional regulation. Our detection of DNase I hypersensitive sites at the CD94 locus that are present only in a cell line expressing endogenous CD94 supports this hypothesis.