iNKT cell regulation of B cell activation in inflammation

Sammanfattning: The ability to combat infections through the generation of specific immune responses is critical to our survival. The immune system can react to and combat virtually any molecule presented to it, including those derived from our own body. The immune system can cause considerable damage to the structures it was designed to protect, thus causing autoimmune disorders. Examples include systemic lupus erythematosus, Sjögren’s syndrome, and rheumatoid arthritis, among many others. Many autoimmune disorders are caused in part by autoreactive antibodies produced by B lymphocytes, and targeting the activation of B lymphocytes thus forms a target for ameliorating disease. Better understanding of how B lymphocytes are activated is essential not only in order to limit autoimmune disease, but also in order to harness their capabilities in the context of generating successful vaccines. The work presented in this thesis deals with B lymphocyte activation in inflammation and in response to glycolipid antigens. The aim was to investigate how this activation is regulated and investigate the possibility of manipulating B cell activation in a desirable way. In papers I and III, mouse models were used to study the regulation of autoreactive and IgE-producing B lymphocytes using IL-18 to induce inflammation. In paper II, model glycolipid antigens were employed to investigate how different types of iNKT cell help affect the outcome for B cell activation, with the prospect of harnessing iNKT cell help as an adjuvants in vaccine therapy. In paper IV, the potential of using glycolipids in order to skew faulty B cell activation in inflammation was investigated. In paper I, iNKT cells were identified as regulators of autoreactive and IgE-producing B cells. Paper II defines quantitative and qualitative differences between cognate and noncogante B cell help provided by iNKT cells. Cognate iNKT cell help, compared to noncognate, expands a larger number of B cells producing the cytokine Interleukin 10. In paper III, mechanisms of iNKT cell regulation of B cell activation were investigated. Neutrophils were found to license iNKT cells to adopt a killing phenotype required to restrict B cell activation in sterile inflammation. In paper IV, B cell activation in inflammation was studied using exogenous glycolipid iNKT cell antigens. Serum antibody levels and germinal center formation were found to be increased in inflammation when iNKT cells were stimulated with glycolipids. In summary, the work presented in this thesis describes mechanisms controlling faulty B cell activation in inflammation. iNKT cells are critical in limiting B cell activation, and this was dependent on interaction with neutrophils. The interaction between neutrophils and iNKT cells plays a previously unappreciated role in the restriction of B cell activation, and thus serves as a potential target for new therapeutic strategies in autoimmune diseases. In addition, the use of glycolipids as vaccine adjuvants, or to target B cell activation is investigated.