Regulation of DC development and functions during steady state and inflammation

Dendritic cells (DCs) are the most important antigen-presenting cells. They bridge innate and adaptive immunity.  They are divided into conventional DC (cDC) and plasmacytoid DC (pDC). However, the developmental origin of pDCs and the signals dictating pDC generation remain incompletely understood. We identified a synergistic effect between IFN-α and Flt3 ligand (FL) in the development of pDCs from common lymphoid progenitors (CLPs). Therefore, pDC-produced IFN-I forms a positive feedback loop for amplifying the generation of pDC from CLPS  (JEM 2013, PLoS One 2015). We also developed a platform to screen for transcription factors that regulated DC development using immortalized hematopoietic stem and progenitor cells (iHSPC) and identified a couple of genes required for pDC development (JOVE 2022). We are currently investigating the detailed mechanisms. Moreover, we also found that TLR stimulation during DC development alters the developmental program by increasing cDC potential but decreasing pDC potential. The functions of the DCs were also altered, with decreased and increased expression of activation markers and cytokine production, depending on the doses of TLR7 stimulation during priming, suggesting features of innate immunity or trained immunity. pDCs also cooperate with B cells to enhance T-independent responses through a p38 MAPK-STAT1 axis. Therefore, we define pDCs as adjuvants for modulating the humoral immunity (J. Immunol. 2023 211: 576).