Modulation of NK cell function by genetically coupled C-type lectin-like receptor/ligand pairs encoded in the human natural killer gene complex

Abstract

Functional responses of natural killer (NK) cells including eradication of "harmful" cells and modulation of immune responses are regulated by a broad variety of activating and inhibitory NK receptors. Whereas the leukocyte receptor complex (LRC) encodes for NK receptors of the immunoglobulin superfamily, genes of C-type lectin-like NK receptors are clustered in the mammalian natural killer gene complex (NKC). Besides the thoroughly studied C-type lectin-like receptors NKG2D, CD94/NKG2x, and members of the murine Ly49 subfamily, the NKC also encodes for NK receptors of the less characterized NKRP1 subfamily. The prototypic mouse NKRP1 receptor is Nkrp1c (also known as NK1.1), while human members of the NKRP1 subfamily are NKRP1A, NKp80, and NKp65. The latter are not straight homologs of mouse NKRP1 receptors, but share distinct subfamily-specific traits classifying them as members of the NKRP1 subfamily. Ligands of the human NKPR1 receptors are likewise C-type lectin-like glycoproteins belonging to the CLEC2 subfamily (i.e., LLT1, AICL, and KACL), and are encoded in the NKC in tight genetic linkage to their respective receptors. Similarly, certain members of the mouse NKRP1 subfamily interact with genetically coupled CLEC2 glycoproteins, while the reasons for this intriguing tight genetic linkage remain unknown. Recent studies provided new and unique insights into the expression, interaction, and signaling of NKRP1 receptors and their ligands, thereby substantially advancing our understanding of their function and biology. Here, we review our current knowledge on NKRP1 receptors and their genetically linked CLEC2 ligands with an emphasis on the human receptor/ligand pairs NKRP1A-LLT1, NKp80-AICL, and NKp65-KACL.

Keywords: C-type lectin-like receptors; NK cell receptors; cytolysis; immunomodulatory; natural killer gene complex.

Figure 1

Ligands of NKC-encoded C-type lectin-like NK cell receptors: C-type lectin fold versus MHC class I fold. (A,B) NK cell receptors encoded in the human (A) or in the mouse NKC (B) engage two structural types of ligands: ligands of NK cell receptors of the NKRP1 subfamily likewise are C-type lectin-like receptors and members of the CLEC2-subfamily encoded in tight genetic linkage to their respective receptors in the NKC (left). Ligands of Nkrp1a, Nkrp1c, Clr-a, Clr-h, and CD69 remain to be identified. Ligands of CD94/NKG2x receptors and Ly49 receptors (mouse only) are MHC class I complexes consisting of a heavy chain, β2-microglobulin, and a peptide (right). The activating NKG2D receptor binds multiple ligands related to the MHC class I heavy chain not associated with β2-microglobulin or antigenic peptides (middle). Symbols “+” and “−” indicate activating and inhibitory function, respectively, of the respective receptors as reported. For Nkrp1a, Nkrp1f, and Nkrp1g, functional consequences of receptor triggering remain to be addressed.

Figure 2

Modulation of NK cell responses by C-type lectin-like receptor/ligand pairs encoded in the human NKC. (A) NKRP1 receptors and their respective ligands of the CLEC2 subfamily are encoded in tight genetic linkage in the telomeric subregion of the human NKC on chromosome 12. Genes (italics) are depicted true to scale with transcriptional orientations indicated by arrows and receptor-ligand pairs by dashed lines. (B) NKRP1A inhibits cytotoxicity and IFN-γ secretion of NK cells upon binding of LLT1 expressed on activated leukocytes. In contrast, NKp80 stimulates effector responses of NK cells: NKp80-AICL interaction promotes TNF and IFNγ production in an activating cross-talk between NK cells and monocytes in the presence of inflammatory cytokines. Further, “resting” NK cells also respond to monokine-activated NK cells in an NKp80-dependent manner by cytokine secretion and cytotoxicity: AICL surfaces on activated NK cells from stores in the Golgi complex, rendering these susceptible to NKp80-mediated cytolysis by bystander NK cells. (C) NKp65 stimulates cytotoxicity and IFNγ secretion of NK-92 cells upon encounter of KACL-bearing target cells. While KACL is specifically expressed by keratinocytes of the human epidermis, cells endogenously expressing NKp65 remain undefined.

Figure 3

Signaling modules of human NKRP1 receptors. (A) ITAM-bearing adaptors such as DAP12 are tyrosine phosphorylated upon ligand binding of the associated receptor chain and subsequently recruit Syk kinases via their SH2 domains (left). CLEC-2 is a prototypical hemITAM-containing CTLR expressed by myeloid cells where two juxtaposed and phosphorylated hemITAM are thought to recruit Syk kinase, thereby bridging two adjacent CLEC-2 monomers. The aminoterminal sequences of both, NKp65 and NKp80, comprise a hemITAM-like sequence with tyrosine 7 being essential for signaling. However, Syk binding to NKp65 remains to be shown and recent studies with NKp80 suggest preferred recruitment of a yet unknown signaling protein different from Syk. (B) Sequence alignment of hemITAM-containing human activating CTLR expressed by NK cells (NKp80), myeloid cells (CLEC-2, Dectin-1, DNGR-1), or yet unknown cells (NKp65), and of ITIM-containing receptors NKRP1A (human) and Nkrp1b (mouse). The core motif YxxL of both hemITAM and ITIM is bolded, the hemITAM-preceding triacidic amino acid sequence underlined, and the first amino acids of the transmembrane domains are in italics. Sequence gaps introduced for alignment are denoted by dashes. HemITAM and ITIM consensus (Ω = L/V/I/S) sequences are also given.