The immune response to infection requires coordination between many cell types for effective pathogen clearance. Cytokines and chemokines serve as secreted proteins that recruit, activate, and regulate immune cells and have been described as the language of the immune system. Just as the study of language can give insight into the human experience and interactions, the study of cytokines and chemokines allows for a better understanding of the immune system.
Influenza virus causes seasonal epidemics that kill 50,000 people in the US each year and occasional pandemics that have killed as many as 100 million people. Many complicated cases of influenza result from dysregulation of cytokine production leading to an inappropriate and deleterious immune response. Defining the roles of individual cytokines is key to understanding the sequelae of influenza infection.
IL-36g is an important cytokine in the immune response to influenza. It served to promote survival of alveolar macrophages during influenza infection by skewing the macrophages towards an M1 phenotype. The rapid loss of alveolar macrophages in Il36g-/- mice led to increased viral titers, pathology, morbidity, and mortality and transfer of WT alveolar macrophages rescued the Il36g-/- mice. Thus, IL-36g acts on alveolar macrophages to enable their survival during respiratory viral infection, decreasing viral replication and pathology.
Preexisitng immunity to influenza can prevent infection, lead to asymptomatic infection, or decrease the severity of symptoms. Unlike neutralizing antibodies, resident memory T cells (TRM) in the lung provide protection across strains of influenza and were found to decrease disease severity during the 2009 H1N1 pandemic. While the factors that lead to the generation of lung TRM cells remain unknown, the chemokine receptor CXCR6 serves to recruit antigen-specific T cells to the airways following respiratory viral infection. CXCR6 is expressed by T cells in the lung and its ligand, CXCL16, is expressed by the airway epithelium in mice and humans. Mice lacking CXCR6 or CXCL16 have decreased airway TRM cells after influenza infection and Cxcr6-/- mice have greater morbidity following secondary infection. The data show the importance of CXCR6 for trafficking of T cells to the airways.
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