Interleukin (IL)-4 and IL-13 were discovered approximately 30 years ago and were immediately linked to allergy and atopic diseases. Since then, new roles for IL-4 and IL-13 and their receptors in normal gestation, fetal development, neurological function and in the pathogenesis of cancer and fibrosis have been appreciated. Studying IL-4/-13 and their receptors has revealed important clues about cytokine biology and lead to the development of numerous experimental therapeutics. Here we aim to highlight new discoveries and consolidate concepts in the field of IL-4 and IL-13 structure, receptor regulation, signaling and experimental therapeutics.

The mechanisms underlying better immune protection by mucosal vaccination have remained poorly understood. In our current study we have investigated the mechanisms by which respiratory virus-mediated mucosal vaccination provides remarkably better immune protection against pulmonary tuberculosis than parenteral vaccination. A recombinant adenovirus-based tuberculosis (TB) vaccine expressing Mycobacterium tuberculosis Ag85A (AdAg85A) was administered either intranasally (i.n.) or i.m. to mice, and Ag-specific CD4 and CD8 T cell responses, including frequency, IFN-γ production, and CTL, were examined in the spleen, lung interstitium, and airway lumen. Although i.m. immunization with AdAg85A led to activation of T cells, particularly CD8 T cells, in the spleen and, to a lesser extent, in the lung interstitium, it failed to elicit any T cell response in the airway lumen. In contrast, although i.n. immunization failed to effectively activate T cells in the spleen, it uniquely elicited higher numbers of Ag-specific CD4 and CD8 T cells in the airway lumen that were capable of IFN-γ production and cytolytic activities, as assessed by an intratracheal in vivo CTL assay. These airway luminal T cells of i.n. immunized mice or splenic T cells of i.m. immunized mice, upon transfer locally to the lungs of naive SCID mice, conferred immune protection against M. tuberculosis challenge. Our study has demonstrated that the airway luminal T cell population plays an important role in immune protection against pulmonary TB, thus providing mechanistic insights into the superior immune protection conferred by respiratory mucosal TB vaccination.

Influenza viral infection is well-known to predispose to subsequent bacterial superinfection in the lung but the mechanisms have remained poorly defined. We have established a murine model of heterologous infections by an H1N1 influenza virus and Staphylococcus aureus. We found that indeed prior influenza infection markedly increased the susceptibility of mice to secondary S. aureus superinfection. Severe sickness and heightened bacterial infection in flu and S. aureus dual-infected animals were associated with severe immunopathology in the lung. We further found that flu-experienced lungs had an impaired NK cell response in the airway to subsequent S. aureus bacterial infection. Thus, adoptive transfer of naive NK cells to the airway of prior flu-infected mice restored flu-impaired antibacterial host defense. We identified that TNF-α production of NK cells played an important role in NK cell-mediated antibacterial host defense as NK cells in flu-experienced lungs had reduced TNF-α expression and adoptive transfer of TNF-α–deficient NK cells to the airway of flu-infected mice failed to restore flu-impaired antibacterial host defense. Defected NK cell function was found to be an upstream mechanism of depressed antibacterial activities by alveolar macrophages as contrast to naive wild-type NK cells, the NK cells from flu-infected or TNF-α–deficient mice failed to enhance S. aureus phagocytosis by alveolar macrophages. Together, our study identifies the weakened NK cell response in the lung to be a novel critical mechanism for flu-mediated susceptibility to bacterial superinfection.

Parenterally administered Mycobacterium bovis BCG vaccine confers only limited immune protection from pulmonary tuberculosis in humans. There is a need for developing effective boosting vaccination strategies. We examined a heterologous prime-boost regimen utilizing BCG as a prime vaccine and our recently described adenoviral vector expressing Ag85A (AdAg85A) as a boost vaccine. Since we recently demonstrated that a single intranasal but not intramuscular immunization with AdAg85A was able to induce potent protection from pulmonary Mycobacterium tuberculosis challenge in a mouse model, we compared the protective effects of parenteral and mucosal booster immunizations following subcutaneous BCG priming. Protection by BCG prime immunization was not effectively boosted by subcutaneous BCG or intramuscular AdAg85A. In contrast, protection by BCG priming was remarkably boosted by intranasal AdAg85A. Such enhanced protection by intranasal AdAg85A was correlated to the numbers of gamma interferon-positive CD4 and CD8 T cells residing in the airway lumen of the lung. Our study demonstrates that intranasal administration of AdAg85A represents an effective way to boost immune protection by parenteral BCG vaccination.Tuberculosis (TB) is the second leading cause of death by infectious disease worldwide. Mycobacterium bovis bacillus Calmette-Guérin (BCG) has been the vaccine of choice given to humans via the skin for over 80 years and has shown variable efficacies of between 0 and 80% in clinical studies (25). In spite of this fact, over 80% of the world population are BCG vaccinees; this vaccine is still being utilized and will likely continue to be utilized in the majority of the world as a part of childhood vaccination programs because of its efficacy in preventing adolescent and disseminated forms of TB, despite the fact that BCG has been shown to have variable efficacies in preventing adult pulmonary tuberculosis (1, 6). Its limited success in control of adult TB has been attributed at least in part to the fact that immune protection by BCG wanes within 10 to 15 years. Much of the past effort has focused on modifying the current BCG vaccine or identifying new vaccine platforms (11,17,22). However, these strategies are unlikely to accomplish long-term TB protection in humans. Furthermore, replacement of the currently used BCG with a different vaccine platform is increasingly considered an unrealistic goal because of the wide clinical usage of BCG and because any phase III clinical vaccine trial would not ethically be allowed to withhold BCG vaccination (12,26). Therefore, the development of strategies that aim to boost BCG-mediated protection represents a priority (15). In this regard, BCG has been shown to be an ineffective booster vaccine for itself and may even be deleterious to protection against TB, as previously shown in clinical and experimental studies (2,5,8). Increasing evidence suggests that effective booster vaccines for BCG immunization ought to be nonmycobacterial (boosters heterologous to BCG) and may inc...