NK cells: tuned by peptide?

Abstract

Natural killer cells express multiple receptors for major histocompatibility complex (MHC) class I, including the killer cell immunoglobulin-like receptors (KIRs) and the C-type lectin-like CD94:NKG2 receptors. The KIR locus is extremely polymorphic, paralleling the diversity of its classical MHC class I ligands. Similarly, the conservation of the NKG2 family of receptors parallels the conservation of MHC-E, the ligand for CD94:NKG2A/C/E. Binding of both CD94:NKG2 heterodimers and KIR to their respective MHC class I ligand is peptide dependent, and despite the evolution of these receptors, they have retained the property of peptide selectivity. Such peptide selectivity affects these two systems in different ways. HLA-E binding non-inhibitory peptides augment inhibition at CD94:NKG2A, while HLA-C binding non-inhibitory peptides antagonize inhibition at KIR2DL2/3, implying that KIRs are specialized to respond positively to changes in peptide repertoire. Thus, while specific KIRs, such as KIR2DL3, are associated with beneficial outcomes from viral infections, viral peptides augment inhibition at CD94:NKGA. Conversely, NKG2A-positive NK cells sense MHC class I downregulation more efficiently than KIRs. Thus, these two receptor:ligand systems appear to have complementary functions in recognizing changes in MHC class I.

Deciphering the killer‐cell immunoglobulin‐like receptor system at super‐resolution for natural killer and T‐cell biology

“…There are different mechanisms by which viral infection can rapidly and radically affect the HLA class I peptide repertoire. Some viruses have evolved to evade NK cell immunity through the selection of mutations in MHC‐presented peptides that enhance binding to inhibitory NK cell receptors including the C‐type lectin‐like CD94:NKG2A heterodimer receptor and KIR2DL3 135, 136. Conversely, virus‐induced changes in peptide repertoire may promote beneficial action through KIR by disrupting HLA class I recognition by inhibitory KIR, releasing constraint on NK cells to mount a positive clearance response to infected cells 135.…”

“…Some viruses have evolved to evade NK cell immunity through the selection of mutations in MHC‐presented peptides that enhance binding to inhibitory NK cell receptors including the C‐type lectin‐like CD94:NKG2A heterodimer receptor and KIR2DL3 135, 136. Conversely, virus‐induced changes in peptide repertoire may promote beneficial action through KIR by disrupting HLA class I recognition by inhibitory KIR, releasing constraint on NK cells to mount a positive clearance response to infected cells 135. Structural analysis of peptide interaction by NK receptors and better understanding of the mechanisms by which viruses evade the NK cell response could assist the development of novel targeted interventions to exploit the antiviral activities of NK cells.…”

The Broad Spectrum of Human Natural Killer Cell Diversity

“…Rather, NK cells are regulated by numerous types of germline-encoded, non-rearranged activating and inhibitory receptors, including two major types of MHC class I-binding receptors: the evolutionarily conserved and non-polymorphic, heterodimeric, C-type lectin-like receptors formed primarily by the combination of CD94 with either NKG2A (inhibitory) or NKG2C (activating); and the large polygenic and highly polymorphic family of killer immunoglobulin-like receptors (KIRs) (Colonna et al, 1999). Whereas CD94/NKG2 heterodimeric receptors bind non-classical MHC class IB molecules such as HLA-E, KIRs bind to classical MHC class IA molecules HLA-A, -B, and -C. These MHC class I-binding receptors regulate NK cell function in an antigen-independent fashion through binding to conserved amino acid residues located outside of the peptide-binding pockets of MHC class I molecules (Das and Khakoo, 2015). …”

Data analysis to modeling to building theory in NK cell biology and beyond: How can computational modeling contribute?

“…NK cell signaling models for other NKRs such as CD16 and 2B4, have been developed recently . Spatial clustering of killer‐cell immunoglobulin‐like receptors (KIRs) and select signaling proteins play an important role in NK cell signaling and activation . Spatially resolved in silico models reviewed in refs.…”