Lower respiratory tract infections are a leading cause of death worldwide. Current vaccines and targeted treatments for such infections, including lung viral infections in particular, are sparse and poorly efficacious. Thus, there is a critical need to improve our understanding of antiviral immune responses in the lung. Morbidity from lung viral infections results from both virus-induced and immune-mediated lung damage, and adaptive immune cells influence both of these processes; they are required for viral clearance, but they are also a main cause of lung immunopathology. The mechanisms that regulate the balance between these protective and pathologic responses are poorly understood. The purpose of this proposal is to provide insight into how antiviral and immunopathologic functions are regulated in the lung parenchyma. We have recently identified type II alveolar cells (AT2) as important regulators of immune responses to lung viral infections. AT2 are abundant epithelial cells present in the distal lung, and unlike most other nonhematopoietic cells, they constitutively express MHC class II (MHCII). AT2 MHCII seems to play an important protective role in the lung, as loss of MHCII on AT2 results in significantly higher morbidity and impaired recovery from influenza (flu) infection in mice. However, unexpectedly, AT2 do not efficiently present antigenic peptides via MHCII. Together this suggests that during viral infection, AT2 MHCII exhibits an active protective function and furthermore that AT2 are prevented from stimulating CD4+ T cells in the lung via MHCII. The experiments outlined in this proposal will elucidate the mechanisms underlying AT2 MHCII protection from flu disease as well as those limiting AT2 MHCII presentation to CD4+ T cells.
Aim 1 will investigate the factors contributing to AT2 MHCII-mediated protection during flu infections by comparing flu-infected mice with and without AT2 MHCII and evaluating the effect of CD8+ T cell depletion, the phenotype and function of lung-infiltrating immune cells, virus titers, and lung pathology.
Aim 2 will assess the mechanisms that limit AT2 MHCII antigen presentation, in particular evaluating the role of the canonical MHCII processing chaperones invariant chain and H2M in restricting AT2 MHCII presentation. These experiments will be complemented by a rigorous training plan focused on achieving my scientific, clinical, and professional goals. Specifically, this plan involves improving my knowledge of advanced laboratory techniques, ability to critically evaluate scientific work, and communication with collaborators and fellow scientists. Additionally, it includes strategies for refining my teaching, leadership, and patient care skills. My training will take place at the University of Pennsylvania, a research institution rich with diverse scientific resources and a highly collaborative atmosphere, under the guidance of the Medical Scientist Training Program as well as my PhD advisor who has an extensive history of mentoring trainees. The plans outlined in this proposal in combination with this environment will foster my development as a physician-scientist.
Lower respiratory tract infections are a major cause of morbidity and mortality worldwide, and immune responses to these pathogens in the lung must be precisely balanced to clear infections while preventing collateral inflammation-induced lung damage. We have recently identified type II alveolar cells (AT2) as important regulators of adaptive immune responses in the lung via their constitutive expression of MHC class II (MHCII). In this proposal we aim to understand the function of MHCII on AT2 in controlling immune responses to lung viral infections, with the ultimate goal of informing the rational development of vaccines and therapies.
