Langerhans cells are required for the priming and induction of an optimal immune response against an acute DNA virus infection

Abstract

Abstract Resistance to ectromelia (ECTV) virus infection is dependent on the induction of a strong type I interferon (T1-IFN) response, which our lab has recently determined is primarily mediated by inflammatory monocytes (iMo) that are recruited to the draining lymph node (dLN). However, the mechanism behind how iMo are recruited is unclear. Accumulation of iMo is dependent on the production of CCL2 and CCL7 by CD11c+MHC-IIhi migratory dendritic cells (skin-mDCs) that originate from the skin of the footpad (initial site of infection), specifically CD103+CD207+ double-positive dermal DCs (DP dermal DCs), CD103−CD207− double-negative DCs (DN dermal DCs) and Langerhans cells. The transport of skin-mDCs to the dLN is dependent on the intrinsic utilization of the TLR9-MyD88-IRF7 axis, highlighting a key role for DNA sensing mechanisms in the skin. Analysis of infected and uninfected skin-mDC subsets reveal differential effector roles between the groups, with DP dermal DCs and Langerhans cells exhibiting high expression of pro-inflammatory cytokines and chemokines. Ablation of skin-mDC recruitment to the dLN with pertussis toxin (Ptx) resulted in a reduction in iMo accumulation and subsequent T1-IFN/pro-inflammatory expression with significantly higher mortality in infected B6 mice (which are normally 100% resistant to ECTV-related mortality). Finally, depletion of Langerhans cells, but not DP dermal DCs, resulted in a significant reduction in iMo accumulation in the dLN and consequently high mortality rates, therefore indicating that Langerhans cells may play an integral role in the priming and breadth of the host immune response against acute viral infections.