The Role of Chronically Stimulated and Senescent T Cells in Autoimmunity

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The Role of Chronically Stimulated and Senescent T Cells in Autoimmunity

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Title: The Role of Chronically Stimulated and Senescent T Cells in Autoimmunity
Author: Ratts, Robert Bruce
Abstract: Myelin-reactive T cells have been hypothesized to play a role in the pathogenesis of MS. If this is the case, these T cells would be expected to be repeatedly stimulated over the course of this disease because of the episodic breakdown of myelin membranes. Continuous stimulation of myelin-reactive T cells may also change the phenotype of these T cells. For example it may drive autoreactive T cells into senescence. Senescent T cells would be unable to divide but may still retain effector functions such as the ability to lyse target cells. The existence of senescent autoreactive T cells in MS patients could explain why therapies that limit the proliferation of T cells have had little effect on the course of MS, particularly later in the course of the disease. Human T cells adopt a CD28-CD57+ phenotype in chronic viral infections and this has been hypothesized to result from chronic stimulation, however this phenotype may also be due to direct viral effects on T cells. Here I make use of human MS patients before and after chronic in vivo administration of the antigen glatiramer acetate to test this hypothesis. Before the initiation of glatiramer acetate treatment, glatiramer acetate -specific CD8 T cells were either CD28-CD57- or CD28+CD57-. This response changed to a predominantly CD28-CD57+ response after one year of continuous stimulation. This phenotype was only observed after chronic stimulation and not in a recall response to mumps. These cells were shown to contain perforin, indicating they likely play a cytotoxic role in vivo. Furthermore CD28-CD57+ CD8 T cells displayed a reduced proliferative capacity indicating they may be senescent or pre-senecent. When myelin-reactive T cell responses were examined a CD28-CD57+ CD8 T cell response could be detected in MS patients but not in healthy controls. These T cells contained mRNA consitant with a cytotoxic role and the abilty to home to the cerebrospinal fluid of MS patients. This observation may explain why therapies that limit the proliferation of T cells have had little effect on the course of MS, particularly later in the course of the disease.
URI: http://hdl.handle.net/2152.5/517
Date: 2006-09-25

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