Hi everybody, I'm new to this forum: I'm a biology student from Switzerland and i would really appreciate if someone could help me with this question. I've tried to answer it, and it would be very kind if someone could tell me if it is right or if there could be a better answer. Thanks you in advance
Here is the question:
Which cells among the list below are affected (would not develop to the stage of mature cells or will present a flaw in one of their functions) by an inactivating mutation in the gene encoding the TAP Transporter (Transporter associated with antigen processing).
Start by describing which effect will be this mutation produce and justify your answers.
T helpers lymphocytes (T auxilliaires ou T CD4)
Cytotoxic T lymphocytes(T CD8)
Macrophages
Natural killer cells (NK)
Lymphocytes B
Neutrophils
My reponse:
A mutation in TAP will modificate the presentation of MHC class 1/peptide composts, as TAP has a role in mediating the peptide add.
Cytotoxic T lymphocytes(T CD8)
TCD8 are dipendent of MHC (HLA in umans) class 1. So as long as gene coding is mutated, TDC8 cell should not be activated, and remain naive.
Natural killer cells (NK) are also dipendent of MHC (HLA in umans) class 1 dipendent. MHC is a NK inhibitor, so as long as gene coding is mutated, NK are being activated, and going to kill cells that don’t present MHC class I.
Macrophages are dipendent to NK interferon gamma (IFNg) moleules producted by NK, so they will probably be affected anda activated.
Sources:
Gadola SD, Moins-Teisserenc HT, Trowsdale J, Gross WL, Cerundolo V. TAP deficiency syndrome. Clinical and Experimental Immunology. 2000;121(2):173-178. doi:10.1046/j.1365-2249.2000.01264.x.
Moreover, granulomatous inflammation of the lungs has not yet been demonstrated in any of the TAP-deficient patients, but it is found in more than 80% of lung biopsies from patients with chronic sarcoidosis.
((en.)->Macrophages?)
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In six patients, the underlying genetic defect was shown to involve the generation of a premature STOP codon
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Analysis of the patients' lymphocyte repertoire in the peripheral blood revealed an expansion of NK and γδ T cells in most patients [2], while CD8+ αβ T cells were present in low numbers [4]. The activity of NK and γδ T cells was further analysed in several patients, because the cytolytic activity of these cells is negatively modulated by inhibitory HLA class I receptors [22,23]. Autoreactive NK and γδ T cells were demonstrated in four patients [2,6]. In two of these patients, activated NK cells were also found in the skin lesions
The pathogenesis of the granulomatous skin lesions may therefore involve activated NK and γδ T cells, which are both capable of promoting a Th1-type inflammatory response leading to granuloma formation
On the other hand, these cell types may also account to some extent for the lack of severe viral infections, as both NK and γδ T cells can recognize virally infected cells without need for TAP-dependent antigen processing [50,51]. The physiologic importance of the residual population of CD8+ αβ T cells in these TAP-deficient patients is currently under investigation.
Activity and Phenotype of Natural Killer Cells in Peptide Transporter (TAP)-deficient Patients (Type I Bare Lymphocyte Syndrome)
• Jacques Zimmer, Lionel Donato, Daniel Hanau, Jean-Pierre Cazenave, Marie-Marthe Tongio, Alessandro Moretta, and Henri de la Salle
J Exp Med 1998 187:117-122. Published January 5, 1998, doi:10.1084/jem.187.1.117
Our results show that NK cells in TAP-deficient patients and normal individuals are phenotypically very similar, apart from the overexpression of CD94–NKG2A in TAP− individuals. Functionally, the greatest differences were observed in resting NK cells. Thus, unlike normal NK cells, TAP− lymphocytes were unable to lyse HLA class I− cells. When normal and TAP− NK cells were activated in vitro, they became cytotoxic towards the same panel of NK-susceptible targets, although TAP− NK cells displayed lower cytolytic activity. Importantly, stimulated TAP− NK cells were cytotoxic to autologous B-LCs.
Abele, Rupert, and Robert Tampë. "Function of the transport complex TAP in cellular immune recognition." Biochimica et Biophysica Acta (BBA)-Biomembranes 1461.2 (1999): 405-419.
A normal cell will display peptides from normal cellular protein turnover on its class I MHC, and CTLs will not be activated in response to them due to central and peripheral tolerance mechanisms. When a cell expresses foreign proteins, such as after viral infection, a fraction of the class I MHC will display these peptides on the cell surface. Consequently, CTLs specific for the MHC:peptide complex will recognize and kill the presenting cell.
Alternatively, class I MHC itself can serve as an inhibitory ligand for natural killer cells (NKs). Reduction in the normal levels of surface class I MHC, a mechanism employed by some viruses during immune evasion or in certain tumors, will activate NK cell killing.
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Under normal conditions class I molecules of the major histocompatibility complex (MHC) present peptides derived from endogenous proteins on the cell surface of every nucleated cell (Fig. 1). During viral infection or malignant transformation, an additional set of peptides bound to MHC class I molecules is delivered to the cell surface for presentation to cytotoxic T lymphocytes (CTL). The recognition of MHC class I molecules (‘self-component’) loaded with peptides derived from ‘non-self’ proteins by CTL via the T cell receptors eventually leads to the lysis/apoptosis of abnormal cells
The pathogens together with their intrinsic proteins are degraded by the major cytosolic proteolysis machinery, the 20S/26S proteasome (for review see [5], [6], [7] and [8]). After cleavage, the peptides are translocated by the transporter associated with antigen processing (TAP) into the endoplasmic reticulum (ER) where assembly of MHC class I molecules and peptides occurs. Stable ternary complexes consisting of heavy chain, β2-microglobulin (β2-m) and bound peptide can leave the ER for surface presentation to T cell receptor.
From wikipedia:
The TAP transporter is found in the ER lumen associated with the peptide-loading complex (PLC). This complex of β2 microglobulin, calreticulin, ERp57, TAP, tapasin, and MHC class I acts to keep hold of MHC molecules until they have been fully loaded with peptides.[4]
During biosynthesis, HLA class I molecules associate with 8–11 amino acid long peptides and β2-microglobulin (β2-M) within the lumen of the endoplasmic reticulum (ER)
Different HLA class I alleles bind to different sets of peptides, most of which are derived from the degradation of cytosolic proteins by a large proteolytic complex called the proteasome. Translocation of peptides derived from degradation of cytosolic proteins into the ER is mediated by the transporter associated with antigen presentation (TAP), a member of the ATP-binding cassette (ABC) superfamily of transporters.
Deletion or mutation of either or both TAP1 and TAP2 proteins severely impairs the translocation of peptides into the ER.
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HLA class I molecules have the dual role of presenting intracellular antigenic peptides to cytotoxic T lymphocytes (CTL), and modulating the activity of cells bearing HLA class I binding receptors, such as natural killer (NK) cells and γδ T cells
