The CD94 and NKG2‐A C‐type lectins covalently assemble to form a natural killer cell inhibitory receptor for HLA class I molecules

Abstract

CD94, a type II membrane protein containing a C-type lectin domain, has been shown to be involved in natural killer (NK) cell-mediated recognition of different HLA allotypes. The inhibitory form of the CD94 receptor has recently been identified by the specific monoclonal antibody (mAb) Z199. Herein, we demonstrate that the inhibitory receptor is in fact a complex formed by the covalent association of CD94 with the NKG2-A molecule (Mr approximately 43 kDa), another member of the C-type lectin superfamily, and that Z199 mAb specifically recognize NKG2-A molecules. Although the NKG2-A-encoding cDNA has been known for several years, the corresponding protein and its possible function remained undefined. Moreover, we show that the NKG2-B protein, an alternatively spliced product of the NKG2-A gene, can also assemble with CD94. Remarkably, both NKG2-A and NKG2-B proteins contain cytoplasmic immunoreceptor tyrosine-based inhibitory motifs (ITIM). This may provide the molecular basis of the inhibitory function mediated by the CD94/NKG2-A receptor complexes.

Synergistic inhibition of natural killer cells by the nonsignaling molecule CD94

“…HLA-E binding to CD94-NKG2A is dominated by the CD94 moiety, and expression of CD94 on the Jurkat transfectants is predominantly in the homodimeric form (22,32). X-ray crystallography suggests that noncovalently linked CD94 homodimers can form spontaneously (35).…”

“…X-ray crystallography suggests that noncovalently linked CD94 homodimers can form spontaneously (35). Furthermore CD94 homodimers have been demonstrated in transfection studies, and CD94 is also expressed on the cell surface in the absence of signaling NKG2 partners (32,36). Thus, there is potential for CD94 to interact with HLA-E in the absence of a signaling partner, and the relatively low sequence identity between CD94 and NKG2A (∼30%) may lead to an alteration in peptide specificity.…”

“…The signaling component of the CD94-NKG2A heterodimer is NKG2A, which possesses two immunoreceptor tyrosine-based inhibitory motifs (ITIMs) within its cytoplasmic tail, whereas CD94 contains no signaling motifs (31,32). We used confocal microscopy to examine the effect of peptides presented by HLA-E on the clustering of CD94 and NKG2A at the immunological synapse formed between effector and target cells.…”

Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect

“…49,[60][61][62][63] CD94 is a product of a single nonpolymorphic gene and essentially lacks a cytoplasmic domain for intrinsic signal transduction capacity. 64 The extracellular and cytoplasmic domains of the NKG2 molecules are structurally diverse, consistent with differences in ligand recognition and signal transduction.…”

Variations of human killer cell lectin-like receptors: common occurrence of NKG2-C deletion in the general population

“…5 NKG2 and CD94 are members of C-type lectin-like NK cell receptors. 6,7 NKG2-A, NKG2-C and NKG2-E form heterodimers with CD94 8,9 and recognize the nonclassical MHC class I molecule, HLA-E, in humans. [10][11][12] NKG2-A/CD94 and NKG2-C, -E/CD94 transmit inhibitory and activation signals into NK cells, respectively.…”