The role of transferrin 1 in lymphocyte activation and serologic memory
An intact immune system depends on molecular signals between and within immune cells to effectively protect the host from infections. Human immunodeficiencies are disorders in which the immune system is unable to respond appropriately to infectious agents or vaccines, leading to recurrent infections that can be fatal. We have identified the first human immunodeficiency caused by a mutation in the gene encoding transferrin receptor 1 (TfR1), a receptor known to be important for importing iron into cells. Patients with this mutation have recurrent infections in the sinuses and lung and are unable to form a long-lasting immune response. We are able to correct some, but not all, of the immune defects by adding a cell-permeable form of iron to bypass the defective TfR1. This suggests that TfR1 has another role in the immune system other than iron import.
Therefore, we propose a novel model of TfR1 function as a receptor with dual roles in activating immune cells: iron import and molecular signaling. We will make a mouse model of this disease to investigate the specific defects leading to this immunodeficiency. These studies will identify how this mutation in TfR1 causes this disease and demonstrate how TfR1 is important for the formation of a normal immune response. In determining the contribution of TfR1 to a normal immune response, these studies may identify new approaches for vaccine development.