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The T-Cell Receptor - III

Date: 11. April 2018

T-Cell Accessory Membrane Molecules – I
Sqadia video is the demonstration of The T-Cell Receptor -III. Although recognition of antigen-MHC complexes is mediated solely by the TCR. CD3 complex, various other membrane molecules play important accessory roles in antigen recognition and T-cell activation. Some of these molecules strengthen the interaction between T cells and APCs or target cells. Some act in signal transduction, and some do both. T cells can be subdivided into two populations expression of CD4 or CD8 membrane molecules. CD4+ T cells recognize antigen that is combined with class II MHC molecules, function largely as helper cells. CD8+ T cells recognize antigen that is combined with class I MHC molecules, function largely as cytotoxic cells. CD8 may take the form of an αβ heterodimer, or an αα homodimer. The monomeric CD4 molecule contains four Ig-fold domains. The extracellular domains of CD4 and CD8 bind to the conserved regions of MHC molecules on antigen-presenting cells (APCs) or target cells.

T-Cell Accessory Membrane Molecules - II
Similar structural data document the mode by which CD4 binds to the class II molecule. The contact between CD4 and MHC II involves contact of the membrane-distal domain of CD4 with a hydrophobic pocket formed by residues from the α2 and β2 domains of MHC II. Whether there are differences between the roles played by the CD4 and CD8 coreceptors remains open to speculation. Despite the similarities in structure, the nature of the binding of peptide to class I and class II molecules differs. Class I has a closed groove that binds a short peptide with a higher degree of specificity. The differences in roles played by the CD4 and CD8 coreceptors are May be due to the differences in binding requirements. 

T-Cell Accessory Membrane Molecules - III
The affinity of T-cell receptors for peptide-MHC complexes is low to moderate, Kd values ranging from 104 to 107 M. This level of affinity is weak compared with antigen-antibody interactions, Kd values ranging from 106 to 1010 M. T-cell interactions do not depend solely on binding by the TCR, Cell-adhesion molecules strengthen the bond between a T cell and an APC or target cell. During activation of a T cell by a particular peptide-MHC complex, There is a transient increase in the membrane expression of cell-adhesion molecules, causing closer contact between the interacting cells Which allows cytokines or cytotoxic substances to be transferred more effectively. Like CD4 and CD8, some of these other molecules also function as signal-transducers.

Three-Dimensional Structures of TCR-Peptide-MHC Complexes
The interaction between TCR and an antigen bound to an MHC molecule is Central to both humoral and cell-mediated responses. A three-dimensional structure has been determined Including TCR α and β chains, an HLA-A2 molecule, an antigenic peptide. The comparisons of the TCR complexed with either class I or class II suggest that there are differences in how the TCR contacts the MHC-peptide complex. From x-ray analysis, the TCR-peptide-MHC complex consists of a single TCR molecule bound to a single MHC molecule and its peptide. The TCR contacts the MHC molecule through the TCR variable domains. The overall area of contact and the structure of the complete TCR variable regions were clear. A space-filling model of the binding site viewed from above Indicates that the peptide is buried beneath the TCR and therefore is not seen from this angle. As predicted from data for immunoglobulins, recognition of the peptide-MHC complex occurs through the variable loops in the TCR structure. TCR molecule fits across the MHC molecule contacting it through a flat surface of the TCR at the “high points” on the MHC molecule. Structures of the peptide-binding regions in class I and class II are similar differences in how they accommodate bound peptide. A comparison of the interactions of a TCR with class I MHC–peptide and class II–peptide reveals a significant difference in the angle at which the TCR molecule sits on the MHC complexes.

Alloreactivity of T-Cells
MHC molecules were first identified because of their role in rejection of foreign tissue. Graft rejection reactions result from the direct response of T cells to MHC molecules, which function as histocompatibility antigens. Because of the extreme polymorphism of the MHC, most individuals of the same species have unique sets of MHC molecules, or histocompatibility antigens, and are considered to be allogeneic. Therefore, T cells respond even to allografts. MHC molecules are considered alloantigens. The alloreactivity of T cells is puzzling for two reasons. First, the ability of T-cells to respond to allogeneic histocompatibility antigens alone appears to contradict all the evidence indicating that T cells can respond only to foreign antigen plus self-MHC molecules. A second problem posed by the T-cell response to allogeneic MHC molecules is that the frequency of alloreactive T cells is quite high. One possible and biologically satisfying explanation for the high frequency of alloreactive T cells is that a particular T-cell receptor specific for a foreign antigenic peptide plus a self-MHC molecule can also cross-react with certain allogeneic MHC molecules. Information relevant to mechanisms for alloreactivity was gained by Reiser and colleagues, who determined the structure of a mouse TCR complexed with an allogeneic class I molecule containing a bound octapeptide. This analysis revealed a structure similar to those reported for TCR bound to class I self-MHC complexes.

Arfeen, Zain
  • Academics: MS
  • Specialization: Biotechnology
  • Current: Research Scholar
  • University: NUST
  • Location: Islamabad, Pakistan
  • Clinical / Teaching Years: 3 / 2
  •  
  • Course: Immunology
  • Course: Pharmacology 

Ms. Zain-ul-Arfeen completed her BS degree in Biotechnology from International Islamic University in 2014 and Technology and later on completed MS in Industrial Biotechnology from NUST in 2016.

She carried out her research in the field of nanotechnology focusing on Point of Care diagnostics and she also remained involved with research in the field of microbiology during her Masters. She has also participated in NUST based entrepreneurial competition with the idea of PapNostics that is built on paper based diagnostics of infections. Currently she is an MLS educator and is being involved in certain research activities at NUST.

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