Mice Lacking Ly49E Show Normal NK Cell Development and Provide Evidence for Probabilistic Expression of Ly49E in NK Cells and T Cells

Aust, Jonathan G.; Gays, Frances; Hussain, Faheem; Butcher, Geoffrey W.; Kist, Ralf; Peters, Heiko; Brooks, Colin G.

doi:10.4049/jimmunol.1003698

Cited by 5 publications

(2 citation statements)

References 46 publications

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“…Ly49F is found predominantly on a subpopulation of activated T cells [6], whilst Ly49E is expressed in the absence of other Ly49s on fetal NK cells, thymic NKT cells, various subpopulations of resting and activated γδT cells, and on activated (but not resting) mature NK cells [7], [8], [9]. Whether the expression of Ly49F is biallelic or monoallelic is unknown, but Ly49E appears to be expressed in a stochastic and predominantly monoallelic manner [10], [11]. Expression of the two genes encoding activating receptors, Ly49D and H, is strictly limited to NK cells, and has been reported to occur in a non-stochastic and biallelic manner [12], [13].…”

Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Transcript Start Sites in Ly49 Genes Reveals an Unexpected Relationship with Gene Function and a Lack Of Upstream Promoters

Gays¹,

Koh²,

Mickiewicz³

et al. 2011

PLoS ONE

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Comprehensive analysis of the transcription start sites of the Ly49 genes of C57BL/6 mice using the oligo-capping 5′-RACE technique revealed that the genes encoding the “missing self” inhibitory receptors, Ly49A, C, G, and I, were transcribed from multiple broad regions in exon 1, in the intron1/exon2 region, and upstream of exon -1b. Ly49E was also transcribed in this manner, and uniquely showed a transcriptional shift from exon1 to exon 2 when NK cells were activated in vitro with IL2. Remarkably, a large proportion of Ly49E transcripts was then initiated from downstream of the translational start codon. By contrast, the genes encoding Ly49B and Q in myeloid cells, the activating Ly49D and H receptors in NK cells, and Ly49F in activated T cells, were predominantly transcribed from a conserved site in a pyrimidine-rich region upstream of exon 1. An ∼200 bp fragment from upstream of the Ly49B start site displayed tissue-specific promoter activity in dendritic cell lines, but the corresponding upstream fragments from all other Ly49 genes lacked detectable tissue-specific promoter activity. In particular, none displayed any significant activity in a newly developed adult NK cell line that expressed multiple Ly49 receptors. Similarly, no promoter activity could be found in fragments upstream of intron1/exon2. Collectively, these findings reveal a previously unrecognized relationship between the pattern of transcription and the expression/function of Ly49 receptors, and indicate that transcription of the Ly49 genes expressed in lymphoid cells is achieved in a manner that does not require classical upstream promoters.

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Section: Introductionmentioning

confidence: 99%

Comprehensive Analysis of Transcript Start Sites in Ly49 Genes Reveals an Unexpected Relationship with Gene Function and a Lack Of Upstream Promoters

Gays¹,

Koh²,

Mickiewicz³

et al. 2011

PLoS ONE

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“…Ly49 knockout mice have been successfully generated for only Ly49Q 129 , which is expressed exclusively on myeloid cells (26), and Ly49E, which is expressed exclusively on liver tissue-resident NK cells but not on conventional splenic NK cells (27,28). Another attempt with an Ly49 targeting construct led to generation of the NKC knockdown (NKC KD ) mouse that contains a concatemerized targeting construct inserted in the NKC (29).…”

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confidence: 99%

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Bern

Beckman

Ebihara

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Natural killer (NK) cells express MHC class I (MHC-I)-specific receptors, such as Ly49A, that inhibit killing of cells expressing self–MHC-I. Self–MHC-I also “licenses” NK cells to become responsive to activating stimuli and regulates the surface level of NK-cell inhibitory receptors. However, the mechanisms of action resulting from these interactions of the Ly49s with their MHC-I ligands, particularly in vivo, have been controversial. Definitive studies could be derived from mice with targeted mutations in inhibitory Ly49s, but there are inherent challenges in specifically altering a single gene within a multigene family. Herein, we generated a knock-in mouse with a targeted mutation in the immunoreceptor tyrosine-based inhibitory motif (ITIM) of Ly49A that abolished the inhibitory function of Ly49A in cytotoxicity assays. This mutant Ly49A caused a licensing defect in NK cells, but the surface expression of Ly49A was unaltered. Moreover, NK cells that expressed this mutant Ly49A exhibited an altered inhibitory receptor repertoire. These results demonstrate that Ly49A ITIM signaling is critical for NK-cell effector inhibition, licensing, and receptor repertoire development.

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Abundant stage-dependent Ly49E expression by liver NK cells is not essential for their differentiation and function

Filtjens

Taveirne

Acker

et al. 2013

Journal of Leukocyte Biology

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The NKR Ly49E has several unique characteristics. Unlike most NKRs, Ly49E is highly expressed on fetal NK cells, whereas expression is decreased on bone marrow-derived NK cells in adult mice. To investigate a possible role for Ly49E in NK cell differentiation and function, we have generated an Ly49E KO mouse. Our results show that bone marrow and splenic NK cells are present in normal numbers in Ly49E KO mice, expressing an unaltered panel of NKRs and differentiation markers. Furthermore, cytokine production and cytotoxicity by these cells are unaffected. Surprisingly, WT DX5(-) liver NK cells express high Ly49E levels in fetal and adult mice. Ly49E(+)DX5(-) liver NK cells transferred into Rag-2(-/-)/gc(-/-) mice maintain high Ly49E expression in the liver and differentiate into DX5(+) NK cells in spleen and bone marrow. Ly49E expression is not crucial for liver NK cell differentiation during ontogeny, as the DX5(-)/DX5(+) ratio, the NKR repertoire, and the granzyme B and TRAIL levels are comparable in Ly49E KO versus WT mice, except for lower TRAIL expression on DX5(-) liver NK cells in 20-day-old mice. The TRAIL-, perforin-, and FasL-mediated cytolysis by liver NK cells is unaffected in Ly49E KO mice. Collectively, we show that in addition to high Ly49E expression on fetal NK cells versus low Ly49E expression on conventional NK cells in adult life, Ly49E remains highly expressed on DX5(-) liver NK cells. However, Ly49E expression does not have a crucial role in differentiation and/or function of these NK cells.

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Mice Lacking Ly49E Show Normal NK Cell Development and Provide Evidence for Probabilistic Expression of Ly49E in NK Cells and T Cells

Cited by 5 publications

References 46 publications

Comprehensive Analysis of Transcript Start Sites in Ly49 Genes Reveals an Unexpected Relationship with Gene Function and a Lack Of Upstream Promoters

Comprehensive Analysis of Transcript Start Sites in Ly49 Genes Reveals an Unexpected Relationship with Gene Function and a Lack Of Upstream Promoters

Immunoreceptor tyrosine-based inhibitory motif–dependent functions of an MHC class I-specific NK cell receptor

Abundant stage-dependent Ly49E expression by liver NK cells is not essential for their differentiation and function

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