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Modulating Cytolytic Responses to Infectious Pathogens
Published in Thomas F. Kresina, Immune Modulating Agents, 2020
Rebecca Pogue Caley, Jeffrey A. Frelinger
Once the peptides are generated in the cytosol, they are transported into the lumen of the endoplasmic reticulum (ER), where they are bound by the class I heavy chains (Figure 1). The major mechanism in the antigen presentation pathway for peptides to be transported is through the transporter complex. The transporter associated with antigen processing (TAP) consists of two subunits, TAP-1 and TAP-2. Cells lines which lack functional TAP molecules show a marked decrease in their cell surface levels of class I [12,15]. Some human leukocyte antigen A2 (HLA-A2) class I complexes which reach the cell surface in the mutant cell line T2 have bound signal sequence derived peptides [16,17]. While the signal sequence pathway provides some of the peptides bound to class I, the majority of peptides entering the antigen presentation pathway enter via the TAP pathway. Transfection of the TAP genes into the TAP-deficient cell lines restores antigen presentation and cell surface MHC levels [18–20]. The subunits of TAP-1 and TAP-2 are 76 and 70 kDa, respectively, and are noncovalently associated. They are thought to function as a dimer, although it is unclear whether high-order multimers occur. The TAP molecules belong to a family of transport proteins which contain an adenosine triphosphate-(ATP)-binding cassette [21]. The TAP-dependent peptide transport is ATP-dependent [22].
The challenges of a circumsporozoite protein-based malaria vaccine
Published in Expert Review of Vaccines, 2021
Deepyan Chatterjee, Ian Andrew Cockburn
In addition to antibodies, CD8+ T cells, and CD4+ T cells were also shown to be key mediators of SPZ induced immunity [27,28]. Notably CD4+ and CD8+ T cells can target epitopes within in CSP. In mice CD8+ T-cell clones targeting the H-2Kd-restricted SYIPSAEKI epitope in PbCSP or the related SYVPSAEQI epitope in P. yoelii CSP (PyCSP) were shown to be able to mediate sterile protection [29,30]. In this case the T cells recognized PbCSP epitopes presented by infected hepatocytes in a transporter associated with antigen processing (TAP) dependent manner indicating that CSP must escape to the host cell cytosol for presentation to CD8+ T cells [31]. However, the development of a strong-PfCSP specific CD8+ T-cell response is likely to be exquisitely dependent on the individual being able to present epitopes from the rather small molecule on their major histocompatibility complex (MHC) class I molecules. Thus, viral vectored vaccines that aim to induce CD8+ T cells that target Plasmodium in the liver have not generally included CSP as an antigen and have relied on responses to other parasite antigens [32–34].
The role of immunoinformatics in the development of T-cell peptide-based vaccines against Mycobacterium tuberculosis
Published in Expert Review of Vaccines, 2020
David Ortega-Tirado, Aldo A. Arvizu-Flores, Carlos Velazquez, Adriana Garibay-Escobar
MHC-I molecules display peptides that come from the degradation of cytosolic proteins both pathogenic and self-proteins. These proteins are ubiquitin ligated with the subsequent degradation of the proteasome into 8–16 aminoacids peptides which are translocated by the TAP complex (transporter associated with antigen processing complex) into the lumen of endoplasmic reticulum (ER) [22,23]. TAP selects peptides on the basis of the size and C-terminal position, giving preference to the peptides with hydrophobic residues in this position [22,23]. The MHC-I molecules are assembled in the ER and coupled to tapasin and the chaperones calreticulin and Erp57 to form the peptide loading complex (PLC). Before peptides can be loaded into MHC-I molecules, they undergo trimming by the aminopeptidase ERAAP to generate 8–10 aminoacids peptides which are preferred by MHC-I molecules [20]. After this process, PLC catalyzes the binding of high affinity peptides to MHC-I molecules. Finally the peptide-MHC-I complex is transported to the surface of the APC (antigen presenting cell) to be presented to a CD8+ T-cell Figure 1.
Development of multi-epitope chimeric vaccine against Taenia solium by exploring its proteome: an in silico approach
Published in Expert Review of Vaccines, 2020
Rimanpreet Kaur, Naina Arora, Majeed Abdulwahid Jamakhani, Shelvia Malik, Pramod Kumar, Farhan Anjum, Shweta Tripathi, Amit Mishra, Amit Prasad
It was reported in various studies that MHC class I supertype A1 and B58 were highly expressed in case of active NCC [22, 23, 24]. Cytotoxic T lymphocyte epitopes or MHC class I binding epitopes were predicted for all proteins by using NetCTL server. NetCTL 1.2 server (http://www.cbs.dtu.dk/services/NetCTL/) was used to predict A1 supertype binding epitopes and NetCTL 4.0 server was used for the prediction of B58 (alleles 1 and 2) binding epitopes. The cutoff score in NetCTL 1.2 server was set at 0.85. A high score in analysis indicates high specificity but low sensitivity of epitopes. The prediction of binding epitope was based on three components: i) prediction of MHC I binding peptides, ii) proteasomal C terminal cleavage and iii) transporter associated with antigen processing (TAP). Artificial neural networks were used for identifying MHC I binding peptides and proteasomal C terminal cleavage site whereas TAP prediction was achieved by weight matrix. The threshold value in NetCTL 4.0 server (http://www.cbs.dtu.dk/) was 0.5% for strong binder and 2% for weak binder (default), only strong binders were considered for further study [25,26].