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Adhesion molecules in T-cell receptor

Adhesion molecules or receptor play key role in many processes involving cellular immunity that included haematopoiesis, migration, activation and finally apoptosis. They are mainly surface glycoproteins and variation among them is mainly due to different pattern of glycosylation. Adhesion molecules play a central role in T cell activation by providing initial temporary attachment of TCR and Antigen bearing MHC on APC.

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It was clearly demonstrated by various studies where complete inhibition of cellular immunity was observed in response to Monoclonal antibody against many of these adhesion molecules.

Cytotoxic CD8 T cells mediated immunity play a key role in viral infection control. It exerts it effect by close cellular interaction with viral infected target cells. Adhesion molecules play a crucial role in driving the effector T cell towards viral infected target cell as well as to establish interaction between TCR and APC. This article briefs the function and properties of some vital adhesion molecules such as LFA-1, ICAM and VLA-4. Further, research carried out to assess the role of adhesion molecules in T-cell receptor is also summarized.

Thymus derived (T) lymphocytes are important regulatory and effectors cells in immune responses. The specificity of cellular immunity is mediated by T cell receptor-CD3 complex interacting with foreign antigen represented by MHC molecule (BARBARA E. , 1988). Activation of T cells leads to functioning of T Cells where it produces various cytokines and cell lyses. In general, CD4+ T cells act as helper cells by producing different effectors molecules after interacting with antigen bearing APC cells, whereas CD8+ cell directly exert it’s effect by killing the antigen bearing APC cells.

Activation and generation of effectors T cells are mediated by TcR-CD3 complex but there are several other surface molecules that play a significant role in immune response and T cell adhesion to APC. Similarly, they have significant role in cell migration, homing and recirculation. Some recent reports indicate the role of these molecules in T cell activation and differentiation. Among many are LFA-1, CD2, CD4, and CD8. Each of these molecules interact with it ligands for example LFA-1 binds to ICAM-1 while LFA-3 bind to CD2 etc. (BARBARA E. , 1988) LFA-1:

The LFA-1 molecule is member of a family of three related proteins found on lymphoid and myeloid cells having common Beta subunits of MW 95000. They are non covalently associated with a unique alpha subunit. Two other members of LFA-1 families are CR3 and p150. LFA-1 molecules are widely distributed on all thymocytes, T cells, B cells, and natural killer cells. Identification of LFA-1 was done when monoclonal antibodies against it was used to inhibit cytotoxic T cell mediated killing and later on it was found to be key molecules which helps in TCR-APC interaction as adhesion molecules.

Similar observation are made where anti LFA- 1 monoclonal antibody inhibits spontaneous aggregation or homotypic adhesions between EB virus mediated activated T cells. This clearly indicates the role of LFA-1 in strengthening the intersection. Any abnormality in expression of these groups of adhesion molecules leads to recurrent bacterial and viral infection and abolished Cytotoxic T cell mediated immunity. (BARBARA E. , 1988) ICAM (Intra cellular Adhesion Molecules): Intercellular Adhesion Molecule-1 (ICAM-1, CD54) is a transmembrane glycoprotein molecule of the immunoglobulin super family.

Each of the molecules is made up of 5 distinct domains and coded by gene present on chromosome 19. It is 80-114 KDa protein having 505 amino acid residues. ICAM associated with receptor of integrin family and having key role in cell signaling and adhesion. A CD8 T cell utilizes temporary interaction between ICAM-1 and LFA-1 to initiate binding of TcR and antigen MHC. This temporary interaction or binding provides sufficient time to T cell to recognize Antigen and respond against it by activation. (BARBARA E. , 1988)

The T-cell lymphocyte migration is influenced by the interactions via the adhesion molecules, the T cell receptor and cytokines. (Hauzenberger D, 1995). The motility of the T cell lymphocytes is very much and critically dependent upon the avidity of the adhesive lymphocyte receptors for endothelial cells ligand and extracellular matrix componenets and the capability of the lymohocytes to undergo a motile response. Hauzenberger D et al. , 1995 discussed that the lymphocytes are rendered motile by adhesion to endothelial cells and ECM components.

This migration, which is considered directed is mediated by beta-1-integrins and special T-cell lymphocytes that possess functional specialization using either alpha 4 beta 1 or alpha 5 beta 1 during chemotaxis and hapotaxis to ECM components. It is also reported that the T cell antigen receptor cannot itself trigger T lymphocyte migration to fibronectin, laminin or collagen type IV but works in hand with signals via alpha 4 beta 1. (Hauzenberger D, 1995) Adhesion molecules and Systemic viral Infection: Research Studies Virus induced changes in the adhesion molecules expression on T-cells were studied by Andersson et al.

, 1997. They studied how the antiviral effector cells migrate into the infectious foci. It was revealed by the FACS (Fluorescent associated Cell sorting) that when systemic lymphocytic choriomeningitis viral infection occurs in cells, various cell adhesion molecules including VLA-4, LFA-1, and ICAM-1 are up regulated on CD8+ cells. The lymph node homing receptor MEL-4 was down regulated during infection, but they observed only marginal changes in CD4+ cells. Further analyses showed that T cells with a changed adhesion molecule profile presented many other cell surface markers, thus indicating a state of cellular activation.

The activation was of IL-2R, and included all virus-specific CTL effectors. The researchers concluded that the hypothesis that indicates that the up regulation of VLA-4 is important for effectors T cell homing to sites of inflammation. (Andersson EC, 1994). In Concanavalin induced Hepatitis, the TNF-? induced expression if Adhesion molecules are under the control of TNFR1. This study was performed by Worl et al. , in 2001. Hepatocellular death by activation of TNFR1 is mediated, apart from this TNF also in responsible for activation of cytokines and adhesion molecules.

Also leads to massive induction of adhesion molecules, like ICAM-1, VCAM-1 and E-selecting in the liver. The study also revealed, that the absence of any of the TNFrs did not change the adhesion molecules expression in the livers of ConA treated mice which leads to the conclusion that the other endothelial cell-activating cytokines up-regulated adhesion molecules expression. This study discusses the critical role of adhesion molecules, such that the upregulaton of adhesion molecules during hepatitis not only contributes to organ injury but also represent defense mechanism. (Dominik Wolf, 2001) Rhinoviruses cause common colds.

This form of common cold has over 100 serotypes, the major group share a single receptor. Lymphocyte function associated molecule 1 (LFA-1) mediates leukocyte adhesion to a wide variety of cell types by binding to intercellular adhesion molecule 1 (ICAM-1). Donald E. Staunton et al. , 1989 demonstrated identity between the receptor for the major group of rhinoviruses and ICAM-1. The studies revealed that a major group rhinovirus binds specifically to purified ICAM-1 and to ICAM-1 expressed on transfected COS cells and binding is blocked by three ICAM-1 monoclonal antibodies (MAb) that block ICAM-1-LFA-1 interaction.

These studies also suggested that the ICAM-1 contact site(s) for LFA-1 and rhinoviruses is identical. Moreover, ICAM-1 MAb block the cytopathic effect in HeLa cells mediated by representative major but not minor group rhinoviruses. The researcher’s concluded that intercellular adhesion molecule 1 is induced by soluble mediators of inflammation, suggesting that the host immune response to rhinovirus may facilitate spread to uninfected cells. (Donald E. Stauntonb, p. 1989) Apart from ICAM1 and LFA-1, other categories of adhesion molecules functioning in T cell receptors include E-selectin and vascular cell adhesion molecule-1.

These adhesion molecules mediate adult T-cell leukemia cell adhesion to endothelial cells. Ishakawa et al. , 1980 studies the adhesion properties of peripheral bold leukemic cells form 10 patients with adult T-cell leukemia to endothelial cells to derive the mechanism of leukemic cell infiltration. ATL cells did express LFA-1 but the expression of VLA-4 was variable. These results, together with the detection of E-selectin expression on the endothelium at ATL skin lesions, indicated that the E-selectin-mediated adhesion is the major pathway for the adherence of ATL cells to endothelial cells.

Moreover, the ligand for E-selectin on ATL cells appears to differ from that on neutrophils. (T Ishikawa, 1993) Bibliography Andersson EC, C. J. (1994). Changes in cell adhesion molecule expression on T cells associated with systemic virus infection. Journal of Immunology , 1237-45. BARBARA E. , B. I. (1988). T cell adhesion molecules. FASEB , 2584-2590. Dominik Wolf, R. H. (2001). TNF–Induced Expression of Adhesion Molecules in the Liver Is Under the Control of TNFR1 Relevance for Concanavalin A-Induced Hepatitis.

The Journal of Immunology , 1300-1307. Donald E. Stauntonb, a. V. (198). A cell adhesion molecule, ICAM-1, is the major surface receptor for rhinoviruses. Cell , 849-853. Hauzenberger D, K. J. (1995). T lymphocyte migration: the influence of interactions via adhesion molecules, the T cell receptor, and cytokines. Crit Rev Immunol. , 285-316. T Ishikawa, A. I. (1993). E-selectin and vascular cell adhesion molecule-1 mediate adult T-cell leukemia cell adhesion to endothelial cells. Blood , 1590-1598.