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The Inducible Defense System: The Induction and Development of the Inducible Defence
Published in Julius P. Kreier, Infection, Resistance, and Immunity, 2022
Michael A. Hickey, Diane Wallace Taylor
All nucleated cells in the body have the ability to process Intercellular proteins into peptides and present them on the cell surface (Figure 8.12). That is, specialized APC are required to process extracellular pathogens (i.e., pathogens that live outside of cells), whereas, intracellular viruses, parasites, and proteins in abnormal tumor cells can be directly processed and presented by the infected cell. In this process, a small amount of protein present in the cytoplasm of the cell is broken down into peptides by a complex of enzymes known as the proteosome. Then, a combination of two proteins, TAP1 and TAP2, transport the peptides made by the proteosome from the cytoplasm into the endoplasmic reticulum. The Class I molecule is made up of two proteins, the Class I protein and an accessory molecule called β-2 microglobulin. The Class 1 molecule and the β-2 microglobulin are made in the endoplasmic reticulum and are able to capture the peptide. This trimolecular complex is then transported from the endoplasmic reticulum to the Golgi and finally to the cell surface.
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].
Major Histocompatibility Complex and Autoimmune Disease
Published in Richard K. Burt, Alberto M. Marmont, Stem Cell Therapy for Autoimmune Disease, 2019
Ursula Holzer, Gerald T. Nepom
HLA class I molecules present peptides, usually eight to nine amino acids in length, to CD8-expressing cytotoxic T-lymphocytes (CTLs) (Fig. 4). The function of the HLA class I molecules is likely primarily to alert T cells to changes inside the cell, e.g., viral infections. Therefore, the presented antigens derive mostly from newly synthesized proteins in the cytosol, e.g., viral proteins.8 These proteins are degraded to peptides in proteolytic complexes called proteosomes. A subset of the resulting peptides are then translocated across the endoplasmatic reticulum (ER) membrane by the transporters associated with antigen processing (TAP)9 encoded by the TAP 1 and TAP2 genes, which are located within the MHC class II region of chromosome 6.2 The peptides transported by TAP are selected to match in length and sequence to the respective MHC class I molecules. Upon loading the antigen on MHC class I molecules in the ER, the whole complex is transported to the surface of the cells.10Figure 4 gives a summary of this process.
Role of platelets and megakaryocytes in adaptive immunity
Published in Platelets, 2021
Genevieve Marcoux, Audrée Laroche, Jenifer Espinoza Romero, Eric Boilard
In addition to MHC I and beta-2 microglobulin (B2-MG), a molecular chaperone for the MHC I complex, mass spectrometry approaches identified 43 proteins related to the “antigen processing and presentation” pathway within the platelet α-granule proteome [63]. Among those proteins, the authors identified antigen peptide transporters 1 and 2 (TAP1 and TAP2), which are involved in the translocation of processed peptides into the platelet ER before they are loaded into MHC I molecules [63]. Components of the peptide loading complex (Erp57, calreticulin, calnexin and tapasin), as well as the T cell co-stimulatory molecules CD40, ICOSL and CD86 (the latter in humans only) [63,64], are found in platelets, suggesting that platelets bear the entire machinery concerned with antigen processing and presentation to T-cells.
Monitoring immunomodulation in patients with sepsis
Published in Expert Review of Molecular Diagnostics, 2021
Evdoxia Kyriazopoulou, Evangelos J. Giamarellos-Bourboulis
The Rapid Recognition of Corticosteroid Resistant or Sensitive Sepsis (RECORDS) trial is comparing the impact of corticosteroids or placebo on mortality and persistent organ dysfunction after 3 months of sepsis onset in subgroups of patients defined by various biomarkers among which molecular ones, like the SRS2 endotype [106]. Working toward a similar direction in the molecular diagnosis and risk stratification of sepsis (MARS) project, Scicluna et al. defined four distinct endotypes, namely MARS 1–4, which were strongly correlated with the monocyte count of these patients [107]. MARS1 was associated with the worst outcome (hazard ratio 1.86; 95%confidence intervals, 1.21 to 2.86) and had decreased expression of genes related to key innate and adaptive immune cell functions. The best characterized genes were encoding for the expression of bisphosphoglycerate mutase (BPGM) and transporter 2, ATP binding cassette subfamily B member (TAP2).
Facing the future: challenges and opportunities in adoptive T cell therapy in cancer
Published in Expert Opinion on Biological Therapy, 2019
Isabelle Magalhaes, Claudia Carvalho-Queiroz, Ciputra Adijaya Hartana, Andreas Kaiser, Ana Lukic, Michael Mints, Ola Nilsson, Hans Grönlund, Jonas Mattsson, Sofia Berglund
Tumor cells have been found to evolve toward reducing or even losing the expression of neoantigens [105], which is a central issue in the T cell ACT. The targeting of normal tissue-restricted antigens found in certain tumors, such as mesothelin in for example pancreatic and ovarian cancer, can be a strategy to circumvent this problem, but this is possible in very few cancer types. Tumor cells have also been described to downregulate HLA class I expression, which complicates antigen recognition by CD8+ T cells [106]. Defects in the proteasome and peptide transporters (TAP-1 and TAP-2) which are responsible for intracellular antigenic processing may contribute to reduced antigen expression on cancer cells [107]. Like in the case of reduced neoantigen expression, certain therapies targeting antigens independent of the proteasome-HLA machinery are not affected by this mechanism, but it is a significant obstacle in many T cell ACTs. Also, the loss of HLA class I expression should enable NK cell-mediated tumor eradication, but the expression of surrogate HLA class I molecules, such as HLA-G, can rescue the cancer cells from detection by NK cells [108]. Furthermore, tumor cells can demonstrate abnormalities in the IFN-γ receptor signaling pathway, leading to the development of IFN-γ insensitivity [109]. Recent evidence also demonstrates that tumors are capable of suppressing TNF signaling within CD8+ T cells, which counteracts T cell-mediated immunity [110].