Signalling Pathways For Inhibition

Despite differences in their proLein sequences and structural conformations, the different families of receptors that set in motion inhibition pathways recognize "self by binding to MHC class I ligands. This recognition of MHC class I molecules provides a means of preventing the killing of normal cells. The known inhibitory receptors contain at least one ITIM through which they are able to suppress the activating signals initiated by ITAM-containing receptors.

ITIMs are found in the intracellular domains of the inhibitory receptors and have a consensus sequence of I(V/L/S)xYxxL(V) [reviewed in 61,62]. Similar to ITAMs, when the receptor binds its ligand, an ITIM is phosphory lated by Src family tyrosine kinases [63.641, Once phos-phorylated, however, ITIMs recruit SH2 domain-containing phosphatases rather than kinases. Instead of phosphorylating motifs and thereby facilitating their interaction with other proteins in the signaling cascade, the phosphatases inhibit progression of the signaling cascade (Fig. 3). SHP-1, a tyrosine phosphatase, directly removes phosphates from proteins phosphory lated by protein kinases. Two alternative views exist on the mechanism of SHP-1-mediated inhibition. SHP-1 may remove the activating phosphate from a central regulator of signaling (e.g., Vavl), or it may remove phosphates from multiple substrates (e.g., LAT, SLP-76, etc.) to affect inhibition. The tyrosine phosphatase SHP-2 can also bind to some ITIMs [65], and its functional role is still under investigation. If signaling through the ITIMs is strong enough, the activation initiated by ITAM-containing receptors may be completely blocked, preventing killing and cytokine release [reviewed in 2].

The ITIM-containing inhibitory receptors in NK cells are the KIR family in humans, the Ly49 family in mice, and the CD94/NKG2A receptor, found in both humans and mice. The expression of these inhibitory receptors on NK cells regulates the NK cell killing of self and provides an important regulatory component to NK cell function.

5.1. Killer cell Ig-like receptor family

Found in humans, members of the family of inhibitory killer cell Ig-like receptors (KIRs) recognize subgroups of the MHC class I molecules HLA-A, HLA-B, or HLA-C. The KIR family comprises at least a dozen genes that have evolved rapidly compared to other immune receptors. Not only do clonal subpopulations of NK cells within an individual present different combinations of inhibitory KIR receptors, but KIR expression among individuals differs significantly [66; reviewed in 67]. Because of these differences in expression, NK cells are able to recognize different combinations of "self," as presented by cells in the form of MHC class I molecules. Despite the variability of ligands that these receptors recognize, each contains ITIMs on the cytoplasmic side of the receptor. Binding of inhibitory KIRs to class I molecules results in inhibition of cytotoxicity through ITIM signaling cascades.

5.2. Ly49 family

Found in mice but not in humans, the Ly49 family of receptors, like the KIRs, recognizes subsets of MHC class I molecules [68], The Ly49 family is composed of at least nine members, and inhibitory Ly49 family members are expressed on the surface of NK cells as homodimers. Like the KIRs, overlapping subsets of these genes are expressed on different clonal subpopulations of NK cells [reviewed in 69].

5.3. CD94/NKG2A

The CD94/NKG2A heterodimer [70] recognizes HLA-E in humans [71-73] or Qalb in mice [74,75], Both HLA-E and Qalb present peptides derived from the leader sequences of other class I molecules (e.g., HLA-A, HLA-B, and HLA-C) that are usually used to present antigens to CD8+ T cells. The cell surface expression of HLA-E and Qalb is dependent upon binding to these leader sequences that are generated by proteolytic degradation in the endoplasmic reticulum. Since intact antigen processing is necessary for surface expression of HLA-E and Qal\ the expression of this peptide provides a means of gauging the integrity of the MHC class I antigen-presentation pathway. When expression of HLA-E is lost, the CD94/NKG2A receptor no longer sends inhibitory signals. Thus, the CD94/NKG2A receptor provides a means for NK cells to monitor the overall expression of MHC class I on a tissue and prevent the escape of a tumour or virally infected cell through down-regulation of MHC class I molecules.

HLA-E can also present a peptide derived from the leader sequence of human heat shock protein 60 (hsp60) [76]. CD94/NKG2A is unable to recognize HLA-E molecules bound to hsp60, thus the display of this peptide on the surface interferes with inhibitory effects of CD94/ NKG2A-HLA-E binding. Human hsp60 is expressed by cells under stress, so the presentation of this peptide provides another means for NK cells to monitor the health of cells that it encounters.

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