| Autoimmune disorders often begin with a T cell response against a self-antigen, which then leads to inflammation and subsequent tissue destruction. For this reason, understanding antigen presentation to T cells is important for gaining insight into autoimmune pathologies. The goal of this thesis was to further the understanding of antigen presentation as it related to models of autoimmunity.; In the lung, I demonstrate that primary antigen presentation occurred directly in the parenchymal tissue by resident CD11c+ antigen-presenting cells. This lung presentation happened as early as six hours post-inhalation of antigen, while presentation in the draining bronchial lymph node was not seen until much later. These studies elucidated a novel way antigen presentation in the lung could occur.; In a separate series of studies using hen egg-white lysozyme (HEL) labeled with radioactive 125Iodine, I developed experiments to understand the cellular distribution of antigen at various times post-immunization. I conclude that following immunization, HEL became concentrated in a limited number of antigen-presenting cells, notably CD11b/c+ but also including B cells. At lower doses of immunization, CD11b/c+ cells still presented all the epitopes of HEL, but B cells were no longer capable of presentation.; Finally, to understand the relationship between diabetes susceptibility and self-antigen levels, I created transgenic mice that bore either varying levels of HEL protein in the pancreas, or that contained transgenic TCR cells with reactivity against chemically minor epitopes of HEL. Using mice with lower and varied levels of HEL on the beta cell, I demonstrated that the beta cell level of autoantigen, and not the whole organ level, was more important for predicting diabetes susceptibility and occurred despite efficient negative selection of the autoreactive 3A9 cells (recognizing the dominant HEL epitope). In contrast, transgenic T cells against a minor epitope of HEL (18-35) were not negatively selected in HEL-bearing mice and subsequently caused diabetes in a predictable fashion. This result, along with data from other arms of this thesis, provides a clearer understanding of the many facets of antigen presentation, particularly in the context of autoimmunity. |
