Highly pathogenic avian influenza viruses (HPAIVs) cause severe disease in humans. Still, the basis for their increased pathogenesis remains unclear. Additionally, the high morbidity in the younger population stays inexplicable, and the recent pandemic H1N1v outbreak in 2009 demonstrated the urgent need for a better understanding about influenza virus infection. In the present study, we demonstrated that HPAIV infection of mice not only led to lung destruction but also to functional damage of the thymus. Moreover, respiratory dendritic cells in the lung functioned as targets for HPAIV infection being able to transport infectious virus from the lung into the thymus. The pandemic H1N1 influenza virus was able to infect respiratory dendritic cells without a proper transport to the thymus. The strong interference of HPAIV with the immune system is especially devastating for the host and can lead to lymphopenia. In summary, from our data, we conclude that highly pathogenic influenza viruses are able to reach the thymus via dendritic cells and to interfere with T lymphocyte development. Moreover, this exceptional mechanism might not only be found in influenza virus infection, but also might be the reason for the increased immune evasion of some new emerging pathogens.