Inhibition of effective anti-tumor immunity by macrophage Bcl6

Abstract

B-cell lymphoma 6 (BCL6) is a transcriptional repressor that is best known for its pivotal function in governing follicular T helper cell and germinal center B cell responses. However, its role in innate anti-viral responses is only now being appreciated. Here we find that BCL6 deficiency in myeloid cells exhibited drastically enhanced host resistance to severe influenza infection, which was independent of IFNAR1 signaling. In contrary to the notion that BCL6 functions to suppress innate inflammation, we find that myeloid BCL6 deficiency diminished lung inflammation without affecting viral loads. Using a series of Cre-transgenic, reporter and knockout mouse lines, we demonstrate that BCL6 deficiency in neutrophils, but not in monocytes or macrophages, attenuated host inflammation and morbidity following influenza infection. Mechanistically, BCL6 disruption resulted in increased expression of a number of genes involved in cellular apoptosis in neutrophils. Consequently, BCL6 deficiency promoted neutrophil apoptosis, specifically at the site of infection. Furthermore, partial neutrophil depletion leaded to diminished pulmonary inflammation and decreased host morbidity. Our results have revealed a previously unappreciated role of BCL6 in modulating neutrophil function and apoptosis at the infected lungs for the regulation of host disease development following influenza infection. Furthermore, our studies indicate that neutrophil survival is tightly regulated in a tissue-specific fashion, thereby influencing inflammation and immunopathology development during acute respiratory viral infection.