1. 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 found a synergism for IFN-I and Flt3 ligand (FL) in pDC development 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). Currently, we are investigating the detailed mechanisms. Moreover, we also found that TLR stimulation during DC development would alter the developmental program by increasing cDC but decreasing pDC potential. The functions of the DCs were also altered, with decreased expression of activation markers, cytokine production, and impaired antigen processing and presentation ability, suggesting that the DCs developed during inflammation were tolerogenic. In addition, mitochondrial dynamics, ROS, and membrane potential were decreased. We are currently deciphering the correlation between mitochondrial dysfunction and impaired DC activity.

2. Innate immune response in host-and-virus interactions

Type I IFN (IFN-I) is the frontline defense and one of the most critical innate immunity against viral infection. IFN-I activates STAT1, STAT2, and STAT3, three family members of the signal transducers and activators of transcription. While STAT1 and STAT2 positively regulate IFN-I-mediated antiviral responses, the role of STAT3 is less clear. Recently, we found that STAT3 negatively regulates IFN-I response independent of its DNA binding and transactivation ability. The N-terminal domain (NTD) of STAT3 is sufficient to suppress IFN-I-mediated gene induction and anti-viral response. STAT3 also inhibits TLR-induced inflammation and IFN-I production (JI 2011). We have identified PLSCR2, a STAT3 interacting protein, to facilitate the suppression effect on IFN-I response. Interestingly, PLSCR2KO mice exhibited an increased inflammatory response and enhanced antiviral activity. These findings define STAT3 as a therapeutic target for viral and inflammatory diseases. (Front. Immunol 2018, Front Immunol. 2019)