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Title: Accessory cell control of T lymphocyte function
Author: Ibrahim, Mohammad Ahmad Abdallah
Awarding Body: University College London (University of London)
Current Institution: University College London (University of London)
Date of Award: 1993
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The interaction between antigen presenting cells (APCs) and T cells is one of the pivotal events in initiation and regulation of an immune response. Central to this is a tripartite molecular interaction between antigen (Ag), molecules of the major histocompatibility complex (MHC) and the Ag specific T cell receptor (TcR). In this study, factors that influence Ag presentation, other than TcR/Ag-MHC interaction, have been studied using a combination of in vitro and in vivo model systems. The results were evaluated in terms of T cell immune responsiveness. An in vitro mixed leucocyte reaction was used to demonstrate that freshly isolated potentially alloreactive murine splenic T cells can be induced, in primary culture, to develop a state of long-lived hypo-responsiveness, both at the level of proliferation and interleukin two secretion. First, this can be induced, in an allo-specific manner, by exposure to allogeneic APCs modified by a chemical cross-linker. This hypo-responsiveness is associated with markedly reduced T cell/APC adhesive clustering interactions despite the lack of a detectable change in lymphocyte function associated antigen one (LFA-1) and intercellular adhesion molecule one (ICAM-1) on the surface of modified APCs. Second, L cells were used which express TcR ligand (transfected MHC class II molecules), but do not express two of the crucial receptor/counter receptor pairs for T cell-APC binding, viz. LFA-1 and ICAM-1, and do not express functional co-stimulatory molecules. These cells could also induce T cell hypo-responsiveness. The results indicate that APCs which do not express "co-stimulatory" signals induce T cell inactivation. The modified allogeneic APCs, which induce T cell hypo-responsiveness in vitro, primed T cells successfully in vivo when they were injected into hind footpads of mice. This apparent paradox was clarified by examining the migratory behaviour of modified and unmodified labelled APCs in vivo. Only a small proportion of label was detected in draining lymph nodes; the kinetics of label recovery were unaffected by fixation of APCs, suggesting that there is no active migration of APCs. Thus, during in vivo experimental allo-sensitization via the subcutaneous route, indirect priming of allogeneic T cells may be the dominant pathway. During the course of these studies, it has become increasingly evident that the interaction of APCs with T cells is a dynamic multimolecular signalling mechanism. Most other studies have focused upon TcR engagement by Ag-MHC molecules which endows Ag specificity to presentation interactions. However, other components of Ag presentation, which are collectively termed co-stimulatory signals (and may include some cell adhesion molecules as well as unidentified factors) may be equally important since they are essential for the full activation and clonal expansion of T cells. Furthermore, these latter pathways may provide regulatory switches for the T cell to differentiate into functionally divergent states, and hence are potentially important for the rational design of immunomodulatory therapies.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available