Efficiency of peptide presentation by dendritic cells compared with other cell types: implications for cross-priming.

Dendritic cells (DCs) play a key role in the induction of cellular immune responses by harvesting antigens from peripheral tissue for cross-priming CD8(+) T cells. It has been demonstrated that apoptotic bodies, whole- or degraded-cell-associated or soluble antigens as well as heat shock protein-bound peptides can be taken up, processed and cross-presented by DCs. Since cells are continuously releasing peptides from their surface MHC molecules, DCs in the tissues are exposed to such peptides and might process and present them to T cells as an additional pathway for cross-priming.

Dissecting cytotoxic T cell responses towards the NY-ESO-1 protein by peptide/MHC-specific antibody fragments.

NY-ESO-1 is a germ cell antigen aberrantly expressed by different tumor types that elicits strong humoral and cellular immune responses, representing one of the most promising candidates for vaccination of cancer patients. A detailed analysis of CD8(+) T cells generated in vaccine trials using NY-ESO-1-derived peptides (157-165 and 157-167) revealed that the dominant immune response was directed against a cryptic epitope (159-167) diverting the immune response from tumor recognition. Only CTL reactivity to the NY-ESO-1(157-165) peptide appeared to be capable of lysing NY-ESO-1/HLA-A0201-expressing tumor cells.

Mono-nucleotide repeats (MNRs): a neglected polymorphism for generating high density genetic maps in silico.

Short, tandemly repeated DNA motifs, termed SSRs (simple sequence repeats) are widely distributed throughout eukaryotic genomes and exhibit a high degree of polymorphism. The availability of size-based methods for genotyping SSRs has made them the markers of choice for genetic linkage studies in all higher eukaryotes. These genotyping methods are not efficiently applicable to mononucleotide repeats (MNRs).

Extended presentation of specific MHC-peptide complexes by mature dendritic cells compared to other types of antigen-presenting cells.

Dendritic cells are known as the most potent antigen-presenting cells for the induction of T cell-mediated immune responses. To discriminate between the presentation of antigens and the co-stimulatory aspects of this high immunostimulatory capacity, we used recombinant antibodies with T cell receptor-like specificity to detect defined MHC-peptide complexes on living cells. Mature human dendritic cells (mDC) were compared with immature DC (iDC), monocytes, CD4(+) T lymphocytes, melanoma cells, T2 cells and B lymphoblastoid cells for their capacity to present MHC class I-restricted tumor-associated T cell epitopes and were found to display the specific peptides two to six times longer than other cells.

Increased expression of human T lymphocyte virus type I (HTLV-I) Tax11-19 peptide-human histocompatibility leukocyte antigen A*201 complexes on CD4+ CD25+ T Cells detected by peptide-specific, major histocompatibility complex-restricted antibodies in patients with HTLV-I-associated neurologic disease.

Human T lymphocyte virus type I (HTLV-I)-associated chronic inflammatory neurological disease (HTLV-I-associated myelopathy/tropical spastic paraparesis [HAM/TSP]) is suggested to be an immunopathologically mediated disorder characterized by large numbers of HTLV-I Tax-specific CD8+ T cells. The frequency of these cells in the peripheral blood and cerebrospinal fluid is proportional to the amount of HTLV-I proviral load and the levels of HTLV-I tax mRNA expression. As the stimulus for these virus-specific T cells are immunodominant peptide-human histocompatibility leukocyte antigen (HLA) complexes expressed on antigen-presenting cells, it was of interest to determine which cells express these complexes and at what frequency.

Recombinant antibodies with MHC-restricted, peptide-specific, T-cell receptor-like specificity: new tools to study antigen presentation and TCR-peptide-MHC interactions.

The advent in recent years of the application of tetrameric arrays of class I peptide-MHC complexes now enables us to detect and study rare populations of antigen-specific CD8+ T cells. However, available methods cannot visualize or determine the number and distribution of these TCR ligands on individual cells or detect antigen-presenting cells (APCs) in tissues. Here we describe a new approach that enables study of human class I peptide-MHC ligand-presentation as well as TCR-peptide-MHC interactions.

Tax and M1 peptide/HLA-A2-specific Fabs and T cell receptors recognize nonidentical structural features on peptide/HLA-A2 complexes.

Both TCRs and Ab molecules are capable of MHC-restricted recognition of peptide/MHC complexes. However, such MHC restriction is the predominant mode of recognition by T cells, but is extremely rare for B cells. The present study asks whether the dichotomy in Ag recognition modes of T and B cells could be due to fundamental differences in the methods by which TCRs and Abs recognize peptide/MHC complexes.

Simultaneous monitoring of binding to and activation of tumor-specific T lymphocytes by peptide-MHC.

The recent advent of peptide-MHC tetramers has provided a new and effective tool for studying antigen-specific T cell populations through monitoring tetramer binding to T cells by flow cytometry. Yet information regarding T cell activation induced by the bound tetramers cannot be deduced from binding studies alone; complementary methods are needed to bridge this gap. To this end, we have developed a new approach that now enables monitoring both binding to and activation of T cells by peptide-MHC tetramers at the single-cell level.

Direct phenotypic analysis of human MHC class I antigen presentation: visualization, quantitation, and in situ detection of human viral epitopes using peptide-specific, MHC-restricted human recombinant antibodies.

The advent in recent years of the application of tetrameric arrays of class I peptide-MHC complexes now enables us to detect and study rare populations of Ag-specific CD8(+) T cells. However, available methods cannot visualize or determine the number and distribution of these TCR ligands on individual cells nor detect APCs in tissues. In this study, we describe for the first time studies of human class I peptide-MHC ligand presentation.

Direct detection and quantitation of a distinct T-cell epitope derived from tumor-specific epithelial cell-associated mucin using human recombinant antibodies endowed with the antigen-specific, major histocompatibility complex-restricted specificity of T cells.

The recent characterization of MHC-displayed tumor-associated antigens that recognize effector cells of the immune system has created new perspectives for cancer therapy. Antibodies that recognize these tumor-associated MHC-peptide complexes with the same specificity as the T-cell antigen receptor will therefore be valuable tools for immunotherapy, as well as for studying antigen presentation in human cancers. Most tumor-associated antigens are expressed in only one or a few tumor types; however, specific T-cell epitopes derived from the Mucin-1 tumor-associated antigen (MUC1) that are widely expressed in many cancers were identified and shown to be recognized by CTLs.

Direct visualization of distinct T cell epitopes derived from a melanoma tumor-associated antigen by using human recombinant antibodies with MHC- restricted T cell receptor-like specificity.

Specificity in the cellular immune system is controlled and regulated by the T cell antigen receptor (TCR), which specifically recognizes peptide/major histocompatibility complex (MHC) molecules. In recent years many cancer-associated MHC-restricted peptides have been isolated and because of their highly restricted fine specificity, they are desirable targets for novel approaches in immunotherapy. Antibodies that would recognize tumor-associated MHC-peptide complexes with the same specificity as the TCR would be valuable reagents for studying antigen presentation by tumor cells, for visualizing MHC-peptide complexes on cells, and eventually for monitoring the expression of specific complexes during immunotherapy.

Resistance to adjuvant arthritis is due to protective antibodies against heat shock protein surface epitopes and the induction of IL-10 secretion.

Adjuvant arthritis (AA) is an experimental model of autoimmune arthritis that can be induced in susceptible strains of rats such as inbred Lewis upon immunization with CFA. AA cannot be induced in resistant strains like Brown-Norway or in Lewis rats after recovery from arthritis. We have previously shown that resistance to AA is due to the presence of natural as well as acquired anti-heat shock protein (HSP) Abs.

Isolation and characterization of human recombinant antibodies endowed with the antigen-specific, major histocompatibility complex-restricted specificity of T cells directed toward the widely expressed tumor T-cell epitopes of the telomerase catalytic subunit.

The recent characterization of MHC-displayed tumor-associated antigensthat recognize effector cells of the immune system has created new perspectives for cancer therapy. Antibodies that recognize these tumor-associated MHC-peptide complexes with the same specificity as the T-cell antigen receptor will therefore be valuable tools for immunotherapy as well as for studying antigen presentation in human cancers. Most tumor-associated antigens are expressed in only one or a few tumor types; however, recently specific T-cell epitopes derived from the telomerase catalytic subunit (hTERT) that are widely expressed in many cancers were identified and shown to be recognized by CTLs derived from cancer patients.