Research

Kevin L. Legge, Ph.D. Assistant Professor of Pathology Laboratory: 112 Medical Research Center Office: 1036 Medical Laboratories Voice: 319-335-6744 Fax: 319-335-8453 Email: kevin-legge@uiowa.edu

Dendritic Cell Immunobiology

The interaction of dendritic cells with naïve T and B cells mediates induction of adaptive immunity to many pathogens.  Recent studies have shown clearance of influenza virus is in part mediated by lysis of virus infected lung epithelial cells by influenza-specific CD8⁺ T cells. While this process is thought to only occur following activation of naïve CD8⁺ T cells through interaction with respiratory dendritic cells (rDC) presenting influenza-derived peptides within the lymph nodes, surprisingly little is known about the migration of rDC to the regional lymph nodes and the rDC-derived factors involved in the activation of naïve CD8⁺ T cells. My research is centered on the role of respiratory dendritic cells in initiating adaptive T cell immunity to respiratory viruses and the interaction of respiratory dendritic cells with and modulation by pulmonary pathogens.

We have recently developed an in situ dye labeling system to identify respiratory resident murine DC and examine their maturation and migration to secondary lymphoid tissues from both the lungs and airways in the normal steady-state and after intranasal influenza infection. This analysis has shown that after induction of pulmonary inflammation by influenza virus infection there is a rapid, but transient, enhanced mobilization/accumulation of mature rDC draining to the PBLN. This wave of accelerated rDC migration to the PBLN is observed only during the first 24-48 hours after pulmonary virus infection and after which rDC become refractory to maturation/migration stimuli. Importantly we have demonstrated that induction of the rDC refractory state by pulmonary inflammatory stimuli inhibits the subsequent mobilization of rDC in response to challenge pathogen infections resulting in a concomitant suppression of the development of pathogen-specific pulmonary T cell responses. Therefore the rDC refractory state may contribute to the high preponderance of secondary infections that are seen following respiratory virus infections. Our laboratory is interested in defining the changes that occur in rDC (after the initial maturation/migration window) that cause their retention in the respiratory tract. To this end we are examining what role inflammatory factors/receptors, that are induced in response to respiratory infection, play in rDC migration/retention with the long-term goal of modulating DC migration/retention in order to allow manipulation of adaptive immunity to natural respiratory infections and vaccinations.

Adaptive T cell immunity to respiratory infections only occurs after rDC encounter respiratory pathogens and are programmed by their interactions with the pathogen to mature/migrate, during the first 24-48 hours after infection, to the regional lymph node and then secrete the growth factors necessary to educate and trigger the adaptive T cell immune response. Our recent work has shown that the degree of virus infection in the respiratory tract can lead to diverse programming of the rDC resulting in differential rDC cytokine production and distinct levels of T cell fitness (i.e. high dose inoculums yield weak CD8⁺ T cell immunity while low dose inoculums yield strong protective CD8⁺ T cell responses). The laboratory is also focused on delineating the factors that control rDC programming in the respiratory tract and how the degree and nature of the pulmonary infection is translated by rDC into changes in the developing pathogen-specific adaptive immune response within the lymph nodes. The outcome of these studies should afford us the opportunity to better target appropriate adaptive immune responses to the respiratory tract, alter respiratory immunopathology, and boost immunity and virus clearance in lethal exposures to respiratory viruses. 

Selected Publications