RESUMO
The interaction of HLA-E with CD94/NKG2A is dependant on the binding of HLA class I signal sequence derived peptides to HLA-E. In the caucasoid population two HLA-E alleles are observed at equal frequencies. Here we study the functional differences between the two HLA-E molecules with regard to cell surface expression, peptide binding, and potential to inhibit lytic activity of a CD94/NKG2A(+) NK cell line. In contrast to the HLA-E(R) allele, the HLA-E(G) allele shows considerable cell surface expression even in the absence of endogenous HLA class I signal sequence derived HLA-E ligands. Eighteen HLA-E allele/HLA-E ligand combinations were analyzed. No correlation between cell surface expression of HLA-E and NK cell inhibition was observed. The peptides present in the signal sequences of HLA-B15, -Cw0402, and -Cw7 bound to both HLA-E alleles but did not lead to an inhibition of NK cell lysis. In our experimental system the peptides A2 and G were not effective with regard to NK cell inhibition when bound to the HLA-E(R) allele. These results may be of functional significance particularly in the placenta where the only HLA-E ligands are derived from HLA-G and -C.
Assuntos
Alelos , Antígenos HLA/imunologia , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Lectinas Tipo C , Antígenos CD/imunologia , Testes Imunológicos de Citotoxicidade , Antígenos HLA/genética , Antígenos de Histocompatibilidade Classe I/genética , Humanos , Células K562 , Ligantes , Glicoproteínas de Membrana/imunologia , Subfamília C de Receptores Semelhantes a Lectina de Células NK , Subfamília D de Receptores Semelhantes a Lectina de Células NK , Oligopeptídeos/metabolismo , Receptores Imunológicos/imunologia , Receptores de Células Matadoras Naturais , Transfecção , Antígenos HLA-ERESUMO
Human CMV has evolved multiple strategies to interfere with immune recognition of the host. A variety of mechanisms target Ag presentation by MHC class I molecules resulting in a reduced class I cell-surface expression. This down-regulation of class I molecules is expected to trigger NK cytotoxicity, which would have to be counteracted by the virus to establish long-term infection. Here we describe that the human CMV open reading frame UL40 encodes a canonical ligand for HLA-E, identical with the HLA-Cw03 signal sequence-derived peptide. Expression of UL40 in HLA-E-positive target cells conferred resistance to NK cell lysis via the CD94/NKG2A receptor. Generation of the UL40-derived HLA-E ligand was also observed in TAP-deficient cells. The presence of a functional TAP-independent HLA-E ligand in the UL40 signal sequence implicates this viral gene as an important negative regulator of NK activity.