Influenza is a major cause of morbidity and mortality, leading to thousands of deaths and many more episodes of respiratory failure annually. Current therapies target the virus and are therefore limited by the capacity of influenza to rapidly evolve and are frequently ineffective in critically ill patients. Clearly, new therapeutic strategies are needed. Respiratory failure in influenza often results from a dysregulated immune response to the virus. Prolonged viral replication or persistent inflammation resulting in immune-mediated lung injury can lead to severe pneumonitis and predisposes the host to secondary infections. Modulation of the host immune response has been proposed as a novel approach to therapy. Thus, a better understanding of host mechanisms that promote viral clearance and prevent immune-mediated lung injury may have powerful therapeutic implications. T cell immunoglobulin and mucin domain 3 (Tim3) is a regulatory protein expressed on innate immune cells, including dendritic cells (DCs), and terminally differentiated T cells. Current evidence suggests that Tim3 is important for both initiation of the innate immune response and termination of the adaptive immune response. We propose that modulation of Tim3 activity can be used to augment host defense and attenuate immune- mediated lung injury in influenza infection. Cross presentation of viral antigens by CD103+ respiratory DCs (rDCs) is critical for the generation of an anti-viral CD8+ T cell response during influenza. Deletion of these cells significantly delays viral clearance and increases disease severity. We present data showing that Tim3 is highly expressed on CD103+ rDCs and that it regulates the function of these cells. We hypothesize that Tim3 promotes the early innate response to influenza by augmenting antigen cross presentation by CD103+ rDCs. In this application, we will define the role of Tim3 on CD103+ rDCs during influenza and delineate the mechanisms by which Tim3 mediates its activity. To facilitate the study of Tim3 on CD103+ rDCs, we have generated a genetically modified mouse that allows cell-specific deletion of Tim3. Specifically we propose (1) To determine the role of Tim3 on CD103+ rDCs in initiating the CD8+ T cell response to influenza, (2) To determine the mechanism by which Tim3 regulates antigen cross presentation by DCs and (3) To define the role of Tim3 on DC subsets in the human lung.
Dendritic cells are important for defense against influenza and play a critical role in activation of anti-viral T cells, which mediate viral clearance, immune-mediated lung injury and therefore determine outcomes. Tim3 is a protein expressed on both dendritic cells and T cells that regulates the immune responses. A better understanding of the role of Tim3 in regulating immune cells in the lung could identify novel therapies for influenza and other inflammatory lung diseases.
