Structure and function of major histocompatibility complex (MHC) class I specific receptors expressed on human natural killer (NK) cells

Abstract

Natural killer (NK) cells express receptors that are specific for MHC class I molecules. These receptors play a crucial role in regulating the lytic and cytokine expression capabilities of NK cells. In humans, three distinct families of genes have been defined that encode for receptors of HLA class I molecules. The first family identified consists of type I transmembrane molecules belonging to the immunoglobulin (Ig) superfamily and are called killer cell Ig-like receptors (KIR). A second group of receptors belonging to the Ig superfamily, named ILT (for immunoglobulin like transcripts), has more recently been described. ILTs are expressed mainly on B, T and myeloid cells, but some members of this group are also expressed on NK cells. They are also referred to as LIRs (for leukocyte Ig-like receptor) and MIRs (for macrophage Ig-like receptor). The ligands for the KIR and some of the ILT receptors include classical (class Ia) HLA class I molecules, as well as the nonclassical (class Ib) HLA-G molecule. The third family of HLA class I receptors are C-type lectin family members and are composed of heterodimers of CD94 covalently associated with a member of the NKG2 family of molecules. The ligand for most members is the nonclassical class I molecule HLA-E. NKG2D, a member of the NKG2 family, is expressed as a homodimer, along with the adaptor molecule DAP10. The ligands of NKG2D include the human class I like molecules MICA and MICB, and the recently described ULBPs. Each of these three families of receptors has individual members that can recognize identical or similar ligands yet signal for activation or inhibition of cellular functions. This dichotomy correlates with particular structural features present in the transmembrane and intracytoplasmic portions of these molecules. In this review we will discuss the molecular structure, specificity, cellular expression patterns, and function of these HLA class I receptors, as well as the chromosomal location and genetic organization.

The human CD94 gene encodes multiple, expressible transcripts including a new partner of NKG2A/B

“…[3][4][5] In order to prevent unwanted responses to normal cells, NK cells also express inhibitory receptors, many of which recognize major histocompatibilty complex (MHC) class I molecules that are expressed by most normal cells. [6][7][8] In general, inhibitory signals override activation signals by recruiting protein tyrosine phosphatases to the proximity of signal initiation. 9,10 The interaction of MHC class I molecules with inhibitory receptors plays a primary role in protecting normal cells from the deleterious effects of NK cell recognition.…”

“…[3][4][5] In humans, the inhibitory receptors expressed by NK cells that interact with MHC class I molecules include members of the Ig superfamily, killer cell Ig-like receptors (KIR) and Ig-like transcripts (ILT), and the CD94/NKG2A heterodimer composed of the covalently associated C-type lectin-like proteins CD94 and NKG2A. 6,11 CD94/NKG2A is expressed on the vast majority of human NK cells and by some CD8 þ T cells. 6 Its ligand is the nonclassical class I molecule human leukocyte antigen (HLA)-E. [12][13][14] Cell surface expression of the CD94/NKG2A receptor is controlled both at the transcriptional and post-transcriptional levels.…”

“…6,11 CD94/NKG2A is expressed on the vast majority of human NK cells and by some CD8 þ T cells. 6 Its ligand is the nonclassical class I molecule human leukocyte antigen (HLA)-E. [12][13][14] Cell surface expression of the CD94/NKG2A receptor is controlled both at the transcriptional and post-transcriptional levels. [15][16][17][18] CD94 can also form activating receptors when paired with NKG2C or NKG2E.…”

“…[15][16][17][18] CD94 can also form activating receptors when paired with NKG2C or NKG2E. 6 Previous work has identified functional isoforms of NKG2A and NKG2E, known as NKG2B and NKG2H, respectively, that are generated by alternative splicing of the relevant pre-mRNAs. 19,20 Although alternative transcripts for CD94 have been reported, 21 it has not been shown if they can be translated, and if so, if they are capable of forming functional receptors with NKG2 family members.…”

Shaping of NK Cell Responses by the Tumor Microenvironment

“…In addition, products of tryptophan degradation such as L-kynerunine and kynerunic acid can directly inhibit various immune cells, including T cells and NK cells. Both membrane-bound and soluble form of HLA-G that are increased in cancer patients bind to the inhibitory receptor ILT-2 expressed by NK cells [72][73][74]. Besides IFN-γ, other cytokines, such as GM-CSF, IL-10 and LIF contribute to the induction of HLA-G expression on malignant cells [75].…”