Peptides isolated from HLA-Cw*0304 confer different degrees of protection from natural killer cell-mediated lysis

Abstract

HLA class I molecules bind peptides derived from proteins degraded in the cytoplasm and display them for surveillance by the immune system. The recognition of HLA class I molecules by natural killer (NK) cells generally inhibits the lytic process. To investigate the role of peptides in the interaction between HLA class I molecules and NK receptors, we first had to identify representative endogenous peptides. Individual peptides bound to HLA-Cw*0304 were isolated and sequenced by tandem mass spectrometry. These peptides ranged in length from 8 to 11 residues and shared an alanine at position 2 and a C-terminal leucine. The murine transporters associated with antigen processing (TAP)-deficient cell line RMA-S was transfected with HLA-Cw*0304 to test whether HLA molecules loaded with a single peptide could deliver the inhibitory signal to NK cells expressing p58.2, which is a killer cell inhibitory receptor known to interact with HLA molecules bearing the HLA-Cw3 public epitope. We found that, in the absence of exogenous peptides, the HLACw*0304 transfectants were killed at levels comparable to untransfected RMA-S cells whereas protection from lysis required both HLA-Cw*0304 heavy chain expression and an exogenously added HLA-Cw*0304-binding peptide. Importantly, not only were HLA-Cw*0304-binding peptides required for protection, but the ability of individual peptides to provide protection differed widely. These studies indicate that the ability to distinguish between subsets of peptides may be a general feature of HLA class I recognition by NK cells.

The double life of NK receptors: stimulation or co-stimulation?

“…KIRs with inhibitory activity recognize ubiquitously distributed MHC class I molecules [42][43][44]; stimulatory KIRs might bind the same ligands, albeit with reduced affinities, or different ligands entirely [45,46]. It is possible that stimulatory KIRs, as has been observed for inhibitory KIRs, bind with higher affinity to MHC class I complexes presenting specific peptides [47,48]. Therefore, the context information provided by stimulatory NKRs, with the exception of NKG2D, appears to be somewhat non-specific.…”

Engagement of CD160 receptor by HLA-C is a triggering mechanism used by circulating natural killer (NK) cells to mediate cytotoxicity

“…HLA-Cw3 monomers were refolded as described (16). HLA-Cw3 recombinant and human ␤2-microglobulin, produced in E. coli, were solubilized in urea and injected together with IAIIPSKKL synthetic peptide (17). Soluble HLA-Cw3 was finally purified by gel filtration on a Sephacryl S-200 column (Amersham Pharmacia).…”

Human-specific evolution of killer cell immunoglobulin-like receptor recognition of major histocompatibility complex class I molecules

“…For example, KIR3DL2 binding to HLA-A3 and HLA-A11 appears to be very peptidedependent, because only one peptide (derived from Epstein-Barr virus (EBV)) has been shown to be permissive for the interaction [43]. Less fastidious are the HLA-C-specific KIRs, for which around 40 per cent of the peptides that bind to HLA-C are compatible with KIR interaction [40,[48][49][50]. That the KIR-and ab TCR-binding sites physically overlap raises the possibility that the individual selection pressures exerted on HLA class I by T-cell and NK-cell immunity can compete with each other (figure 3).…”