Genetically linked C-type lectin-related ligands for the NKRP1 family of natural killer cell receptors

Abstract

The natural killer (NK) gene complex (NKC) encodes orphan lectin-like NK cell receptors that may explain uncharacterized NK cell specificities. Unlike other NKC-encoded receptors that recognize molecules with major histocompatibility complex (MHC) class I folds, here we show that mouse Nkrp1d and Nkrp1f bind specific C-type lectin-related (Clr) molecules. Nkrp1d mediated inhibition when recognizing Clrb, a molecule expressed in dendritic cells and macrophages. Nkrp1 (official gene name, Klrb1) and Clr are intertwined in a genetically conserved NKC region showing recombination suppression, reminiscent of plant self-incompatibility loci. Thus, these findings broaden the 'missing-self' hypothesis from solely involving MHC class I to including related NK cell receptors for lectin-like ligands, and reflect genetic strategies for biological self-recognition processes in other species.

Reconstructing immune phylogeny: new perspectives

“…Certain KIRs and Ly49 proteins recognize MHC class I molecules. Other NK-cell receptors recognize a broad range of stress-induced molecules and other non-classical MHC molecules 63,64 , as well as viral gene products 65,66 and other NK-cell receptors 67 . NK-cell activity has a broad phylogenetic distribution extending to invertebrates 68 .…”

Two major groups of rat NKR‐P1 receptors can be distinguished based on chromosomal localization, phylogenetic analysis and Clr ligand binding

“…Clrb is constitutively expressed by hematopoietic cells and inhibits cytolytic activity of NKR-P1B/ D-expressing NK cells [10,11]. The activating NKR-P1F receptor has been shown to bind another Clr molecule, Clrg, by the use of a reporter assay and soluble recombinant proteins [11], but the functional consequence of this interaction remains obscure.…”

“…Clrb is constitutively expressed by hematopoietic cells and inhibits cytolytic activity of NKR-P1B/ D-expressing NK cells [10,11]. The activating NKR-P1F receptor has been shown to bind another Clr molecule, Clrg, by the use of a reporter assay and soluble recombinant proteins [11], but the functional consequence of this interaction remains obscure. In human, the NKR-P1A receptor binds a Clr orthologue termed lectin-like transcript 1(LLT1), which is able to specifically inhibit NK cytolytic activity and cytokine production [12][13][14].…”

“…Although the NKR-P1 family has expanded to include both activating and inhibitory members in rodents, it consists of only one member in several other mammalian species, including in human [6]. The nature of their ligands has been controversial [7,8], but it has recently been shown that members of another KLR-related receptor family, the C-type lectin-related (Clr) molecules [9], also termed C-type lectin 2D (CLEC2D), can act as ligands for certain NKR-P1 molecules [10,11]. The Clr gene family also shows considerable expansion in rodents and the Clr genes are interspersed with the Nkrp1 genes in the proximal (centromeric) part of the NKC.…”

Deletion of PI3K-p85α gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells

“…14 Although the activating ligands for Nkrp1c have yet to be determined, the inhibitory ligands for its related family members Nkrp1d and Nkrp1f have been defined as the Clr family of C-type lectins. 15 NK1.1 physically associates with FcRg to mediate its signal. 16 The interplay between the activating and inhibitory receptors regulates NK cell functions.…”