The role of CD4+T cells in airway remodeling in experimental asthma /

The aim of this work was to investigate the role of CD4 + T cells, central to airway inflammation in asthma, in airway remodeling. Structural changes that occur in asthmatic airways in association with inflammation include an increase in airway smooth muscle mass, which participates in causing airway hyperresponsiveness. We aimed to gain further insights into the mechanisms that may link inflammation with remodeling using a rat model of experimental asthma. We hypothesized that CD4+ T cells drive airway smooth muscle remodeling. Adoptive transfer of CD4+ T cells from ovalbumin-sensitized rats induced increased proliferation and inhibition of apoptosis of airway myocytes in naive recipients upon repeated antigen challenge, which resulted in an increase in airway smooth muscle mass. CD4+ T cells genetically modified to express green fluorescent protein were localized by confocal microscopy in juxtaposition to airway smooth muscle cells, suggesting that CD4 + T cells may modulate smooth muscle cell function through direct cell-cell interaction in vivo. We subsequently co-cultured antigen-stimulated CD4+ T cells with cell cycle-arrested airway smooth muscle cells and demonstrated by flow cytometry that CD4+ T cells induce myocyte proliferation, dependent on T cell activation and direct T cell/myocyte contact. Reciprocally, direct cell contact prevented activation-induced T cell apoptosis as well as spontaneous apoptosis of resting T cells, suggesting T cell/myocyte cross-talk. Our data demonstrate that CD4+ T cells drive airway smooth muscle remodeling in experimental asthma, and suggest that a mechanism involving a direct "synapse" participates in CD4+ T cell regulation of myocyte turnover and induction of remodeling. The goal of genetically modifying CD4+ T cells involved technical challenges relevant to the field of gene therapy and are dealt with in detail in this thesis. Retroviral gene transduction coupled with antigenic stimulation wa