Disease relevance of Klrc1

• Antibody-dependent blockade of this Qa-1-NKG2A interaction resulted in potent NK-dependent elimination of activated autoreactive T cells and amelioration of experimental autoimmune encephalomyelitis [1].
• Blockade of NKG2A ligation resulted in the enhancement of lung injury induced by CD8+ effector cell recognition of alveolar Ag in vivo in the absence of infectious virus [2].

High impact information on Klrc1

• The major histocompatibility complex class Ib protein, Qa-1(b), serves as a ligand for murine CD94/NKG2A natural killer (NK) cell inhibitory receptors [3].
• The heterodimeric CD94/NKG2A receptor, expressed by mouse natural killer (NK) cells, transduces inhibitory signals upon recognition of its ligand, Qa-1(b), a nonclassical major histocompatibility complex class Ib molecule [4].
• Mouse NKG2A maps adjacent to CD94 in the heart of the NK complex on mouse chromosome six, one of a small cluster of NKG2-like genes [5].
• Individual Ly49 genes are stochastically expressed by NK subsets and are expressed in a monoallelic fashion, but little is known about the mechanisms underlying CD94/NKG2A expression [6].
• Of interest, alpha-GalCer was inferior to OCH in priming iNKT cells for subsequent restimulation because alpha-GalCer-induced interferon gamma (IFN-gamma) up-regulated Qa-1b expression and Qa-1b in turn inhibited iNKT-cell activity via its interaction with the inhibitory CD94/NKG2A receptor [7].

Biological context of Klrc1

• Thus, self-tolerance of neonatal NK cells cannot be attributed to CD94/NKG2A expression [6].
• Here we report the cloning of murine NKG2A, B and C. The deduced amino acid sequence of mouse NKG2A contains only one consensus cytoplasmic immunoreceptor tyrosine-based inhibitory motif (ITIM) [8].
• In addition, a high frequency of granzyme A, B, C and G transcripts (for clone Bpp9) or transcripts for CD94 and NKG2A (for clone Bpp19) were expressed differentially, together with transcripts that mapped to, so far, unassigned regions of the mouse genome that may be further novel genes [9].
• A role for DNA hypomethylation and histone acetylation in maintaining allele-specific expression of mouse NKG2A in developing and mature NK cells [10].
• However, expression of CD94 and NKG2A transgenes partially inhibited early events of T cell activation [11].

Anatomical context of Klrc1

• This is the first report to show the critical role for NK-cell receptors in controlling iNKT-cell responses and provides a novel strategy to augment the therapeutic effect of iNKT cells by priming with OCH or blocking of the CD94/NKG2A inhibitory pathway in clinical applications [7].
• These subtle effects suggest that CD94/NKG2A-mediated inhibition of T cells may be limited to particular circumstances or may synergize with other receptors that are similarly up-regulated [11].
• Co-expression of Qa-1(b) and D(k) on target cells significantly inhibited cytotoxicity of D(k)-specific cytotoxic T lymphocytes generated by mixed lymphocyte reaction, indicating that Qa-1(b) on antigen-presenting cells interacts with CD94/NKG2A on CD8 T cells and regulates classical MHC class I-restricted cytotoxic T cells [12].

Physical interactions of Klrc1

• The Qa-1/Qdm complex is the primary ligand for CD94/NKG2A inhibitory receptors expressed on a major fraction of natural killer (NK) cells [13].

Other interactions of Klrc1

• TCR and CD28 were re-expressed more rapidly than the inhibitory NK-cell receptors CD94/NKG2A and Ly49, temporally rendering the primed iNKT cells hyperreactive to ligand restimulation [7].
• Over 75% of them expressed Ly49C, I, or NKG2A, which are thought to recognize self-class I MHC (H-2b) [14].
• By contrast, anti-NK1.1 inhibited the lytic activity and failed to stimulate a calcium response in cells expressing the NKG2-A/NKR-P1C chimeric receptor [15].
• The expression of CD94/NKG2A was rapidly initiated in naive CD8(+) T cells responding to peptide Ags in vitro and on many of the naive T cells that proliferate when transferred into lymphopenic (Rag-1(-/-)) hosts [11].
• TGF-beta also increases CD94/NKG2A expression on memory CD8 T cells that are re-exposed to antigen [16].

Analytical, diagnostic and therapeutic context of Klrc1

• Molecular cloning of mouse NKG2A and C [17].
• We developed a single-cell RT-PCR method to analyze expression of all known Ly49 and NKG2A genes in individual NK cells and determined the receptor repertoires of NK cells from adult and neonatal (1-wk-old) C57BL/6 mice [14].
• Flow cytometry experiments with Qa-1(b) tetramers and NK target cell lysis assays demonstrated that CD94/NKG2A discriminates between Qa-1(b) complexes containing peptides with substitutions at nonanchor positions P4, P5, or P8 [3].

References