Langerhans Cells in Autoimmunity: New Perspectives in Function and Homeostasis
- Author(s): Gutierrez, Miguel-Angel
- Advisor(s): Singh, Ram Raj
- et al.
Langerhans cells (LC) are the premier antigen presenting cells on epithelial surfaces. The key to LCs’ functions is their residence in peripheral tissues as well as their capacity to migrate to local draining lymphoid organs. The present dissertation’s goal is to elucidate the specific roles LCs play in the context of autoimmunity, by employing a mouse model genetically prone to develop multi-organ autoimmune disease, in which LCs can be traced and selectively depleted in vivo.
Previous studies have elucidated LCs’ ability to induce tolerance against skin-specific self-antigen and as well as to protect against the development of autoimmune skin inflammation. However, LCs’ role in other, non-skin, organs where they are present, such as in cornea on eye surface and in gastric and genital mucosa, remains largely unknown. We found that LCs were altered in distribution and density in the cornea of autoimmune-prone mice. Importantly, aselective depletion of LCs led to acceleration of corneal inflammation, along with increased T cell activation and proliferation in eye-draining lymph nodes. These data allowed us to show for the first time that LCs play a protective role against corneal autoimmune disease, potentially through inhibition of T cell activation in a tissue-specific manner.
Homeostatic migration of LCs from their tissue of residence to local draining lymph nodes is a hallmark of LC biology, however, the underlying mechanisms are largely unclear. We studied mechanism of LCs migration using models of autoimmune dermatitis, where LC migration was previously shown to be defective prior to the onset of clinical disease. We demonstrate that skin-resident dendritic epidermal T cells are reduced in the epidermis of these autoimmune-prone mice, and that a glycolipid that ameliorates skin inflammation restores DETCs and LC migration. This rescue of LC migration in autoimmune mice by skin-resident dendritic epidermal T cells is mediated, at least in part, via CD40–CD40L signaling. Such ‘local’ control of migratory behavior of tissue-resident dendritic cells can regulate systemic immune response in a tissue-specific manner, which has important implications for protection against inflammation, autoimmune diseases and graft rejection, and vaccination against cancers and infections.