GM-CSF promotes T regulatory cell-inducing, lung resident dendritic cells at steady state

Authors

• V Savy
• P Stein
• CJ Williams

Abstract

Dendritic cells (DCs) bridge the innate and adaptive immune systems by capturing antigens and presenting the derived peptides to antigen-specific T cells. Tissue resident conventional DCs (cDCs), which develop from FMS-like tyrosine kinase 3 ligand (FLT3L)-dependent DC precursors (preDCs), are activated upon exposure to antigens and associated adjuvants. In mouse lung, there are two major cDC subsets, CD103+ cDC1 and CD11b+ cDC2. The latter is a heterogeneous population, and this heterogeneity has hindered a comprehensive understanding of lung DC development and function. We recently reported that lung resident cDC2s are marked by cell surface CD301b and represent the major cDC2 subset during steady state. Other cDC2 subsets, including Ly-6C+ immature and CD200+ migratory cells, are only present during inflammation, which accompanies allergic sensitization through the airway. Single cell RNA sequencing (scRNA-Seq) and adoptive transfer experiments revealed that Ly-6C+ immature cDC2s are the precursors of both CD301b+ lung resident and CD200+ migratory cDC2s. However, the molecular mechanisms that direct these distinct cell fates are unknown. We show here that GM-CSF overproducing mice have significant increases in CD301b+ resident cDC2s compared with wild-type mice. Conversely, mice lacking the GM-CSF receptor in DCs display reduced numbers of CD301b+ cDC2s. Finally, we found that ex vivo, CD301b+ cDC2s induce T regulatory cell (Treg) differentiation from naïve T cells. Thus, at steady state, GM-CSF promotes lung homeostasis by directing the maturation of lung resident cDC2s and Tregs.

Scientific Focus Area: Immunology

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