Study on the role of interleukin-7 as mucosal immune modulator in the lung

Abstract

Among the emerging respiratory infectious disease, influenza A virus (IAV) is one of the major threat to global public health, and is responsible for anuual seasonal epidemics as well as four pandemics in the last century. IAV has ability to generate new strain of virus by point-mutation and gene-reassortment. Due to this reason, current strategy such as vaccination and anti-viral agent would have limited protective efficacy against emerging IAV strain. To overcome this limitation, alternative strategy for development of universal IAV prophylaxis is strongly needed. The risk of IAV infection is conferred by excessive host-mediated immunopathology and defective IAV-specific T cell mediated immunity, which results in acute respiratory dysfunction and mortality. Thus, modulation of mucosal immunity and induction of broad-spectrum of IAV-specific immunity would be a promising approach to prevent severe IAV-associated complications. In this study, I demonstrated that the intranasal treatment of Fc-fused IL-7 had universal prophylactic effect against lethal influenza infection by modulation of mucosal immune response and generation of cross-protective IAV specific immunity. Firstly, I showed that intranasal pretreatment of Fc-fused IL-7 alone can protect immunologically naïve mice against lethal influenza infection until 5 weeks post treatment. When treated intranasally, the Fc-fused IL-7 entered into the lung interstitium through neonatal Fc receptor mediated transcytosis, and stimulated various mucosal immune cells, especially resulting in sustained increase of pulmonary resident memory phenotype (TRM-like) CD4 and CD8 T cells. Experiments using T cell-deficient mice, specific depletion of T cell subset and FTY720 revealed that those IL-7-primed TRM-like cells are critically involved in the protective effect of Fc-fused IL-7 by induction of IAV-specific CD8 T cell response and modulation of pulmonary inflammation. Secondly, intranasal delivery of Fc-fused IL-7 enhanced generation of cross-protective M2e-specific T cells and antibodies for co-administered octameric M2e-peptide vaccine, and conferred significant protective effect against lethal IAV infection of heterologous IAV. Based on the two studies described above, I suggest the mucosal delivery of Fc-fused IL-7, either treated alone or used as an adjuvant, as a promising countermeasure for pandemic IAV and other emerging respiratory infectious diseases.