Structural Basis for Recognition of Cellular and Viral Ligands by NK Cell Receptors

Abstract

Natural killer (NK) cells are key components of innate immune responses to tumors and viral infections. NK cell function is regulated by NK cell receptors that recognize both cellular and viral ligands, including major histocompatibility complex (MHC), MHC-like, and non-MHC molecules. These receptors include Ly49s, killer immunoglobulin-like receptors, leukocyte immunoglobulin-like receptors, and NKG2A/CD94, which bind MHC class I (MHC-I) molecules, and NKG2D, which binds MHC-I paralogs such as the stress-induced proteins MICA and ULBP. In addition, certain viruses have evolved MHC-like immunoevasins, such as UL18 and m157 from cytomegalovirus, that act as decoy ligands for NK receptors. A growing number of NK receptor–ligand interaction pairs involving non-MHC molecules have also been identified, including NKp30–B7-H6, killer cell lectin-like receptor G1–cadherin, and NKp80–AICL. Here, we describe crystal structures determined to date of NK cell receptors bound to MHC, MHC-related, and non-MHC ligands. Collectively, these structures reveal the diverse solutions that NK receptors have developed to recognize these molecules, thereby enabling the regulation of NK cytolytic activity by both host and viral ligands.

Practical NK cell phenotyping and variability in healthy adults

“…The cell stress sensing activating receptor, NKG2D, was expressed on both CD56 bright and CD56 dim NK cells although the mean percent positive and MFI were higher on CD56 bright (73.3%; MFI 34) than CD56 dim NK cells (47.6; MFI 17) (Fig 2b, c). NKp30 and NKp46 are natural cytotoxicity receptors (NCR) that can promote NK cell activation and can participate in the recognition of rapidly dividing as well as certain types of virally infected cells [17]. The expression of NKp46 was diffuse although the mean percentage and MFI of NKp46 positive cells was higher on CD56 bright (76.4%; MFI 49.4) than CD56 dim (40.5%; MFI 20.3) NK cells.…”

NKG2D Receptor and Its Ligands in Host Defense

“…All of the NKG2D ligands have α1 and α2 extracellular domains with homology to MHC class I molecules (MICA and MICB proteins also possess an α3 domain), but none bind peptides or β2-microglobulin. Structures of many of the mouse and human ligands in complex with NKG2D have been reported (reviewed in (34)). NKG2D binds with affinities varying from 10 −6 – 10 −9 M to these diverse NKG2D ligands, some with only ~25% amino acid homology, by an “adaptive fit” mechanism, rather than inducing conformational changes in the ligands (reviewed in (34)).…”

Colonization and effector functions of innate lymphoid cells in mucosal tissues

“…On the other hand, many MHC class I molecules act as inhibitory ligands for CD94-NKG2A and KIR2DL1/2/3 (CD158a/b) [146–148]. This recognition inhibits NK cells from killing uninfected normal cells [149]. NK cells also regulate immune responses through production of cytokines such as IFN-γ and TNF-α [150].…”