Presentation Of T-cell Epitopes Research Articles

T-cell epitope prediction methods: an overview.

The scientific community is overwhelmed by the voluminous increase in the quantum of data on biological systems, including but not limited to the immune system. Consequently, immunoinformatics databases are continually being developed to accommodate this ever increasing data and analytical tools are continually being developed to analyze the same. Therefore, researchers are now equipped with numerous databases, analytical and prediction tools, in anticipation of better means of prevention of and therapeutic intervention in diseases of humans and other animals. Epitope is a part of an antigen, recognized either by B- or T-cells and/or molecules of the host immune system. Since only a few amino acid residues that comprise an epitope (instead of the whole protein) are sufficient to elicit an immune response, attempts are being made to identify or predict this critical stretch or patch of amino acid residues, i.e., T-cell epitopes and B-cell epitopes to be included in multiple-subunit vaccines. T-cell epitope prediction is a challenge owing to the high degree of MHC polymorphism and disparity in the volume of data on various steps encountered in the generation and presentation of T-cell epitopes in the living systems. Many algorithms/methods developed to predict T-cell epitopes and Web servers incorporating the same are available. These are based on approaches like considering amphipathicity profiles of proteins, sequence motifs, quantitative matrices (QM), artificial neural networks (ANN), support vector machines (SVM), quantitative structure activity relationship (QSAR) and molecular docking simulations, etc. This chapter aims to introduce the reader to the principle(s) underlying some of these methods/algorithms as well as procedural and practical aspects of using the same.

Multiple, Non-conserved, Internal Viral Ligands Naturally Presented by HLA-B27 in Human Respiratory Syncytial Virus-infected Cells

Cytotoxic T lymphocyte (CTL)-mediated death of virus-infected cells requires prior recognition of short viral peptide antigens that are presented by human leukocyte antigen (HLA) class I molecules on the surface of infected cells. The CTL response is critical for the clearance of human respiratory syncytial virus (HRSV) infection. Using mass spectrometry analysis of complex HLA-bound peptide pools isolated from large amounts of HRSV-infected cells, we identified nine naturally processed HLA-B27 ligands. The isolated peptides are derived from six internal, not envelope, proteins of the infective virus. The sequences of most of these ligands are not conserved between different HRSV strains, suggesting a mechanism to explain recurrent infection with virus of different HRSV antigenic subgroups. In addition, these nine ligands represent a significant fraction of the proteome of this virus, which is monitored by the same HLA class I allele. These data have implications for vaccine development as well as for analysis of the CTL response.

Endogenous Processing and Presentation of T-cell Epitopes from Chlamydia trachomatis with Relevance in HLA-B27-associated Reactive Arthritis

Chlamydia trachomatis triggers reactive arthritis, a spondyloarthropathy linked to the human major histocompatibility complex molecule HLA-B27, through an unknown mechanism that might involve molecular mimicry between chlamydial and self-derived HLA-B27 ligands. Chlamydia-specific CD8(+) T-cells are found in reactive arthritis patients, but the immunogenic epitopes are unknown. A previous screening of the chlamydial genome for putative HLA-B27 ligands predicted multiple peptides that were recognized in vitro by CD8(+) T-lymphocytes from patients. Here stable transfectants expressing bacterial fusion proteins in human cells were generated to investigate the endogenous processing and presentation by HLA-B27 of two such epitopes through comparative immunoproteomics of HLA-B27-bound peptide repertoires. A predicted T-cell epitope, from the CT610 gene product, was presented by HLA-B27. This is, to our knowledge, the first endogenously processed epitope involved in HLA-B27-restricted responses against C. trachomatis in reactive arthritis. A second predicted epitope, from the CT634 gene product, was not detected. Instead a non-predicted nonamer from the same protein was identified. Both bacterial peptides showed very high homology with human sequences containing the HLA-B27 binding motif. Thus, expression and intracellular processing of chlamydial proteins into human cells allowed us to identify two bacterial HLA-B27 ligands, including the first endogenous T-cell epitope from C. trachomatis involved in spondyloarthropathy. That human proteins contain sequences mimicking chlamydial T-cell epitopes suggests a basis for an autoimmune component of Chlamydia-induced HLA-B27-associated disease.

Human anti-idiotypic antibodies can be good immunogens as they target FC receptors on antigen-presenting cells allowing efficient stimulation of both helper and cytotoxic T-cell responses.

Anti-idiotypic antibodies that mimic tumour-associated antigens can stimulate anti-tumour T-cell responses. In this article, we have studied the role of Fc in the presentation of T-cell epitopes by 2 anti-idiotypic antibodies, 105AD7 and 708. The human monoclonal antibody 105AD7, which mimics CD55, stimulated strong in vitro T-cell proliferation, gammaIFN secretion and redirected cytotoxicity in unprimed T cells from healthy donors. However, removal of the Fc region of the anti-idiotype reduced the sensitivity of the assay 1,000-fold, as did inhibiting Fc uptake of the anti-idiotype by an excess of human IgG. The mouse anti-idiotype 708, which mimics CEA, failed to stimulate in vitro T-cell responses on unprimed T cells from healthy donors. However, when a human IgG1 Fc region replaced its mouse Fc region, the anti-idiotype induced T-cell proliferation, gammaIFN secretion and redirected cytotoxicity in lymphocytes from unimmunised donors. Human anti-idiotypes are therefore good immunogens since they target Fc receptors on antigen-presenting cells, allowing efficient stimulation of both helper and cytotoxic T-cell responses. The immunogenicity of other anti-idiotypes may therefore be enhanced by human Fc targeting of antigen-presenting cells.