Abstract
On healthy cells the non-classical HLA class Ib molecule HLA-E displays the cognate ligand for the NK cell receptor NKG2A/CD94 when bound to HLA class I signal peptide sequences. In a pathogenic situation when HLA class I is absent, HLA-E is bound to a diverse set of peptides and enables the stimulatory NKG2C/CD94 receptor to bind. The activation of CD8+ T cells by certain p:HLA-E complexes illustrates the dual role of this low polymorphic HLA molecule in innate and adaptive immunity. Recent studies revealed a shift in the HLA-E peptide repertoire in cells with defects in the peptide loading complex machinery. We recently showed that HLA-E presents a highly diverse set of peptides in the absence of HLA class Ia and revealed a non-protective feature against NK cell cytotoxicity mediated by these peptides. In the present study we have evaluated the molecular basis for the impaired NK cell inhibition by these peptides and determined the cell surface stability of individual p:HLA-E complexes and their binding efficiency to soluble NKG2A/CD94 or NKG2C/CD94 receptors. Additionally, we analyzed the recognition of these p:HLA-E epitopes by CD8+ T cells. We show that non-canonical peptides provide stable cell surface expression of HLA-E, and these p:HLA-E complexes still bind to NKG2/CD94 receptors in a peptide-restricted fashion. Furthermore, individual p:HLA-E complexes elicit activation of CD8+ T cells with an effector memory phenotype. These novel HLA-E epitopes provide new implications for therapies targeting cells with abnormal HLA class I expression.
Highlights
The discrimination of self and non-self by the immune system is based on the recognition of specific ligands by their cognate immune receptors
The balance between stimulatory and inhibitory signals elicited from the NKG2C/CD94 and NKG2A/CD94 receptor is highly dependent on the peptide that is presented by their common ligand human leucocyte antigen (HLA)-E [36]
To determine how distinct p:HLA-E complexes influence the binding to the NKG2/CD94 receptors, we determined the differences in binding to recombinant sNKG2A/CD94, or sNKG2C/CD94 receptors consisting of their soluble ectodomains at physiological conditions
Summary
The discrimination of self and non-self by the immune system is based on the recognition of specific ligands by their cognate immune receptors. The absence of HLA class I molecules on the cell surface makes the cell prone to a surveillance mechanism executed by NK cells that patrol for HLA class I expression and attack cells that lack HLA class I molecules on their surface, a mechanism known as “missing self” [14] Viruses such as hCMV evolved a strategy to evade NK cell killing by down-regulation of HLA class I molecules. This strategy is mediated by the virus-derived protein gpUL40 that provides a peptide ligand to induce surface expression of the HLA class Ib molecule HLA-E. These peptides showed diverse sequences, but none of the peptides was derived from an HLA class signal sequence
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