UBC Theses and Dissertations
Shaping of the T cell repertoire by self and foreign antigens Tsai, Kevin
T cells are an indispensable component of the immune system. Any perturbation in T cell function may have severe consequences such as immune deficiency, autoimmunity or development of malignancies. T cell receptors and the signals transduced by them are critical for many aspects of T cell biology. A diverse yet tolerant TCR repertoire is essential for the proper functioning of the immune system. Herein, we investigated several factors that regulate T cell immune responses, autoimmunity and the TCR repertoire. We investigated whether co-delivery of autoantigen insulin along the natural killer T cell antigen αGalCer within novel liposomes could prevent T1D in non-obese diabetic mice. We found that subcutaneous injection of such liposomes could potently stimulate NKT cells to activate other immune cell types. Further, their subcutaneous administration reduced the frequency of islet-reactive T cells and conferred protection against diabetes. These experiments suggest that using liposomes to co-deliver autoantigens along with αGalCer may prove to be a valuable for the prevention of autoimmune diseases. Next, we examined whether the expression of two types of TCRs by individual CD8 T cells could contribute to autoreactivity and autoimmunity. We compared the reactivity against the model autoantigen OVA between CD8 T cells capable of expressing two types of TCRs (bi-allelic, TCRα⁺/⁺) versus those restricted to a single TCR (mono-allelic, TCRα+/-). Bi-allelic CD8 T cells exhibited increased proliferative capacity and autoreactivity relative to mono-allelic CD8 T cells. Altogether, our results suggest that dual TCR-expressing CD8 T cells evade tolerance and participate in the pathogenesis of autoimmunity. Lastly, we studied the role of MUC2 mucin in regulating CD8 T cell tolerance against oral antigens. Wild type and MUC2-deficient (Muc2-/-) mice were orally gavaged with ovalbumin (OVA) to examine the impact of dietary antigens on CD8 T cells. We found that oral administration resulted in rapid systemic dissemination of OVA in the blood and tissues of Muc2-/- mice, and culminated in the deletion of OVA-specific thymocytes. Consequently, our findings suggest that MUC2-deficiency results the shaping the TCR repertoire of developing thymocytes by intestinal luminal antigens.
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