The natural suppression of respiratory CD8 T cell memory by monocyte-derived dendritic cells (moDC)

Abstract

Abstract Heterosubtypic CD8 T cell immunity can protect mice and humans against reinfection with highly mutagenic viruses like influenza. Studies in mice attribute this protection to CD8+ tissue resident memory cells (TRM) residing in the lung and airways. However, both live attenuated influenza vaccines and natural influenza infection fail to protect humans from seasonal influenza. Interestingly, unlike TRM derived from other mucosal infections, the majority of TRM in the lung parenchyma are devoid of CD103 and CD69 expression, suggesting bona-fide TRM are either not generated or stably maintained. Using a mouse model, we show respiratory infection evokes the selective migration of CD11c+CD11b+CD103+CCR2+PD-L1hi moDCs to the lung-draining lymph nodes in response to a variety of pathogens (influenza, RSV, VSV) 72–96 hours post infection, coordinate with T cell priming. These moDC develop in the context of systemic and intranasally VSV challenged animals and influenza infected mice, but only emigrate from the bone marrow after respiratory infection. Lymph node immigration is coordinate with regional CCL2 expression. Importantly, the selective depletion of moDCs using CCR2-DTR bone marrow chimeras numerically enhances CD103+CD69+ TRM formation and increases local IFN-ɣ and TNF-α after heterologous virus challenge. In summary, our studies show that moDCs selectively suppress TRM formation after respiratory infection. Ongoing studies seek to understand the molecular mechanism(s) used by moDCs to alter CD8 T cell programming and TRM development.