The selective downregulation of class I major histocompatibility complex proteins by HIV-1 protects HIV-infected cells from NK cells.

To avoid detection by CTL, HIV encodes mechanisms for removal of class I MHC proteins from the surface of infected cells. However, class I downregulation potentially exposes the virus-infected cell to attack by NK cells. Human lymphoid cells are protected from NK cell cytotoxicity primarily by HLA-C and HLA-E.

Human CD16 as a lysis receptor mediating direct natural killer cell cytotoxicity.

In addition to their role in peptide antigen presentation, class I MHC proteins also play a critical role in inhibiting natural killer (NK) cytotoxicity through interaction with NK inhibitory receptors. Thus, NK cells are cytotoxic to virus-infected and tumor cells that have lost class I MHC protein expression. However, the nature of the receptors involved in the triggering of lysis of target cells is poorly understood.

The transmembrane sequence of human histocompatibility leukocyte antigen (HLA)-C as a determinant in inhibition of a subset of natural killer cells.

Molecular interactions with the extracellular domains of class I major histocompatibility complex proteins are major determinants of immune recognition that have been extensively studied both physically and biochemically. However, no immunological function has yet been placed on the transmembrane or cytoplasmic amino acid sequences of these proteins despite strict conservation of unique features within each class I major histocompatibility complex locus. Here we report that lysis by a subset of natural killer (NK) cells inhibited by target cell expression of human histocompatibility leukocyte antigen (HLA)-Cw6 or -Cw7 was not inhibited by expression of chimeric proteins consisting of the extracellular domains of HLA-C and the COOH-terminal portion of HLA-G.

Natural killer activating receptors trigger interferon gamma secretion from T cells and natural killer cells.

Proliferation of human CD4+ alphabeta T cells expressing a natural killer cell activating receptor (NKAR) has been shown to be enhanced, particularly in response to low doses of antigen, if the target cells present appropriate human class I major histocompatibility complex (MHC) molecules. Here, we show that NKAR also enhance proliferation and killing of target cells by subsets of CD8+ alphabeta and CD8+ gammadelta T cells, as well as by NK cells. Strikingly, interferon gamma secretion from all of these types of lymphocytes was markedly increased by interaction of the NKAR with their MHC class I ligands, independently of enhancement of proliferation.

Identification of shared tumor-associated antigen peptides between two spontaneous lung carcinomas.

CTLs recognize antigenic peptides bound to MHC class I Ags on the cell surface of tumor cells. Tumor-associated Ag (TAA) peptides are 8 to 10 amino acids long and can be derived from normal, mutated, or viral proteins. The majority of T cell-defined Ags have been identified in human melanoma cells.

Multiple receptors for HLA-G on human natural killer cells.

HLA-G is the putative natural killer (NK) cell inhibitory ligand expressed on the extravillous cytotrophoblast of the human placenta. Killing of the class I negative human B cell line 721.221 by NK cells is inhibited by the expression of HLA-G.

Natural killer cell lines kill autologous beta2-microglobulin-deficient melanoma cells: implications for cancer immunotherapy.

Cancer vaccines used to generate specific cytotoxic T lymphocytes are not effective against tumor cells that have lost or suppressed expression of their class I major histocompatibility complex proteins. This loss is common in some cancers and particularly in metastatic lesions. We show that beta2-microglobulin-deficient class I-negative melanoma variants derived from patients undergoing specific T cell therapy are lysed by heterologous as well as autologous natural killer (NK) lines and clones, but not by specific T cells.

Impaired spontaneous endocytosis of HLA-G.

HLA-G is a class Ib (non-classical) major histocompatibility complex (MHC) protein expressed at the maternal-fetal interface that inhibits natural killer (NK) cell-mediated lysis in an allotype-independent manner. Here we report that the spontaneous endocytosis of HLA-G is severely reduced because of its short cytoplasmic tail. Class I (classical) MHC proteins on the surface of B cell transfectants detected by primary and secondary antibodies underwent endocytosis at a moderate rate, whereas HLA-G, chimeric proteins consisting of the extracellular domains of HLA-C with the C-terminal sequence of HLA-G, or glycophosphatidylinositol-tailed HLA-C proteins, were not efficiently internalized.

Self and viral peptides can initiate lysis by autologous natural killer cells.

Natural killer (NK) cells are inhibited by specific allotypes of class I major histocompatibility complex ligands recognized by polymorphic inhibitory receptors (e.g., NKIR1 and NKIR2).

The class I MHC homologue of human cytomegalovirus inhibits attack by natural killer cells.

Recognition and destruction of virus-infected cells by class I major histocompatibility complex (MHC) restricted cytotoxic T lymphocytes (CTL) is a central part of the immune system's attempts to control and eliminate virus infection. It is therefore not surprising that many viruses have evolved strategies to interfere with the processing and presentation of peptide antigen on class I MHC molecules (reviewed in ref. 1).

The binding site of NK receptors on HLA-C molecules.

The protection of cells expressing class I HLA molecules from NK lysis is mediated by natural killer cell inhibitory receptors (NKIR). Using site-directed mutagenesis, residues on HLA-C that determine the locus specificity (alphaVal-76), allotype group specificity (a dimorphism alphaAsn-80/Lys-80), and affinity of NKIR binding (a second pair of dimorphisms, alphaAla-73, Asp-90 or alphaThr-73, Ala-90) have been identified. Thus the "footprint" of the NKIR on the alpha1 helix of the class I MHC molecule HLA-C and its associated beta strands are similar in position to the site occupied by superantigens on and behind the alpha1 helix of the class II MHC molecule HLA-DR1, but further toward its C-terminus.

Human NK cells: their ligands, receptors and functions.

The expression, or lack thereof, of class I MHC glycoproteins has a marked influence on natural killer cell function. Cells which do not express class I MHC molecules are susceptible to lysis by NK cells, and transfection of these targets with class I MHC genes can render these cells resistant to NK attack. This inhibition of NK-killing is mediated by a novel family of receptors expressed mainly on NK cells, but also found on some T-cells.

Enhancement of class II-restricted T cell responses by costimulatory NK receptors for class I MHC proteins.

An important feature of the human immune system is the ability of T cells to respond to small quantities of antigen. Class II major histocompatibility complex (MHC)-restricted T cells that expressed a costimulatory natural killer (NK) cell receptor for class I MHC proteins were cloned. In the presence of low doses of superantigen, the proliferative response of these T cell clones was three- to ninefold greater when the T cells were costimulated by way of the NK receptor.

Protection from natural killer cell-mediated lysis by HLA-G expression on target cells.

The outermost layer of the human placenta is devoid of classical class I human leukocyte antigens (HLA-A, HLA-B, and HLA-C) and class II proteins (HLA-DR, HLA-DQ, and HLA-DP). Although this prevents recognition by maternal T lymphocytes, the lack of class I molecules leaves these cells susceptible to attack by natural killer (NK) cells. However, trophoblast cells directly in contact with the maternal tissues express the class I molecule HLA-G, which may be involved in protecting the trophoblast from recognition by NK cells.

Protection from lysis by natural killer cells of group 1 and 2 specificity is mediated by residue 80 in human histocompatibility leukocyte antigen C alleles and also occurs with empty major histocompatibility complex molecules.

Recognition of major histocompatibility complex class I molecules by natural killer (NR) cells leads to inhibition of target cell lysis. Based on the capacity of different human histocompatibility leukocyte antigen (HLA)-C and HLA-B molecules to inhibit target cell lysis by NK lines and clones, three NK allospecificities have been defined: NK1 and NK2 cells are inhibited by different HLA-C allotypes and NK3 cells by some HLA-B allotypes. The NK1 and NK2 inhibitory ligands on target cells correspond to a dimorphism of HLA-C at residues 77 and 80 in the alpha 1 helix: Asn77-Lys80 in NK1 and Ser77-Asn80 in NK2 inhibitory ligands.

Expression of two H-2K genes, syngeneic and allogeneic, as a strategy for potentiating immune recognition of tumor cells.

Metastatic clones of some tumors manifest an impaired expression of class I major histocompatibility complex (MHC) antigens. High metastatic, low immunogenic Lewis lung carcinoma clones (C57BL-H-2b origin) express low levels of the H-2Kb MHC antigen. These cells metastasize spontaneously in C57BL/6J mice.

Regression of established murine carcinoma metastases following vaccination with tumour-associated antigen peptides.

The cure of micrometastases following surgery is the major goal of cancer immunotherapy. We have recently isolated tumour-associated antigen (TAA) peptides, MUT 1 and MUT 2, derived from a mutated connexin 37 gap-junction protein, from the malignant 3LL-D122 murine lung carcinoma. We now report that synthetic MUT 1 or MUT 2 induces effective antitumour cytoxic T lymphocytes.

CTL induction by a tumour-associated antigen octapeptide derived from a murine lung carcinoma.

Many mouse and human tumours express major histocompatibility complex (MHC) class I-associated antigens that constitute targets for syngeneic cytotoxic T lymphocytes (CTL). Genes encoding such antigens were isolated from a mouse mastocytoma and from human melanomas by genetic methods. Isolation and characterization of MHC class I-associated peptides has enabled specific anchor residues to be identified that are typical of peptides that bind to distinct class I molecules.

H-2K double transfectants of tumor cells as antimetastatic cellular vaccines in heterozygous recipients. Implications for the T cell repertoire.

In this study we demonstrate that antitumor CTL repertoire restricted to a single MHC class I allele is higher in homozygous than in heterozygous mice. Consequently, transfection of two parental H-2K genes, but not of a single H-2K gene into a highly metastatic H-2K-negative tumor clone, resulted in abrogation of metastatic properties in F1 recipients. Clones of the 3LL carcinoma, which are low H-2Kb expressors, are nonimmunogenic and highly metastatic.