Therapeutic alteration of T cell development: Modulating diabetogenic and regulatory T cells in the treatment of type 1 diabetes mellitus

Abstract

In this dissertation we investigate the role of avidity in the T cell selection process by examining the impact of signal modulation on T cell and/or NKT cell development. Projects discussed herein (including peptide, anti-CD1d, and hydrocortisone (HC) therapy) examine how changes in avidity can be used to explore potential therapies for Type 1 diabetes mellitus (T1DM). In the case of peptide therapy, we find that fetal thymic organ culture (FTOC), treated with exogenous diabetes related GAD peptides, lose their ability to generate T cell responses to GAD treatment peptides. Also, peptide therapy is shown to inhibit T1DM in vitro (ivT1DM) and in vivo. The abnormally high level of GAD peptides that are presented during peptide therapy treatment are thought to increase avidity between peptide specific T cells and selecting cells during thymic education, leading to increased negative selection of those T cells. In the case of anti-CD1d, FTOC from C57BL/6 (B6) and non-obese diabetic (NOD) mice, when treated with 10 μg/mL of anti-CD1d, show divergent responses to treatment. In response to anti-CD1d, "normal" B6 FTOC shows decreased T cell development and NKT production. Conversely, "poor signaling" NOD mice show no major impact on general T cell development but instead show increases in NKT cell production. Also, treatment with anti-CD1d is shown to inhibit diabetes in our ivT1DM model. These effects are thought to be due to increases in avidity generated through anti-CD1d related increased TCR expression. Changes in avidity caused by anti-CD1d treatment are thought to generate increased negative selection in B6 FTOC, while the same avidity increases are thought to increase positive selection (without increasing negative selection) in "poor signaling" NOD FTOC. In the case of HC treatment, B6 FTOC treated with HC show changes in T cell yield, maturity, and TCR Vβ usage. Research with HC indicates that signal inhibitors have the capacity to change T cell development in a dose and time dependent manner. Based on this work, selection signal inhibitors or enhancers may have the capacity to change T cell development in a fashion that decreases autoimmune T cells and/or enhances regulatory NKT cell development.