1. Role of Type I IFN in FL- dependent DC development

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 genes 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. Cooperation between dendritic cells and B cells

B cells express various TLRs, and TLR stimulation activates and differentiates B cells into plasma cells to produce antibodies. However, the molecular mechanisms by which TLR signaling molecule dictates antibody response remain elusive. We found STAT1 as an essential regulator for differentiation but not the activation of MZ B cells in response to TLR stimulation.  MZ B lacking STAT1 reduces antibody response compared to WT control. Moreover, STAT1KO mice are more susceptible to blood-borne infection of Streptococcus pneumoniae. Therefore, we have defined the essential role of STAT1 for MZ B-mediated humoral immune response (JEM 2016).  Moreover,  DCs, including pDC and cDC, could cooperate with B cells to promote TLR-induced B cell activation, proliferation and differentiation and antibody production in an IFN-I-dependent manner.  One of the mechanisms is through the p38 MAPK-STAT1 axis to promote B cell response (JI 2023).

3. Innate immune response in host and viral 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 in addition to enhanced antiviral activity. These findings define STAT3 as a therapeutic target for viral and inflammatory diseases. (Front. Immunol 2018, Front Immunol. 2019)

last updated 11/07/2022

PhD students

Yu-Ling Hsiao

Master's students

2nd year

Kuan-Hsiang Liu, Yuan-Chih Li

1st year

Jui-Yu Chang, Shi-Zong Hsu

Last updated Sep. 16, 2024

1. Hsin-Hsiang Chen,  Ya-Ru Yu, Yu-Ling Hsiao , Shun-Hua Chen and Chien-Kuo Lee Plasmacytoid dendritic cells enhance T-independent B cell response through a p38 MAPK-STAT1 axis. The Journal of Immunology, 2023, 211: 576-590.
2. Yu-Ling Hsiao, Hans Häcker, and Chien-Kuo Lee Study of dendritic cell development by short hairpin RNA-mediated gene knockdown in a hematopoietic stem and progenitor cell line in vitro. J. Vis. Exp. 2022 181:e62730, doi:10.3791/62730.
3. Chien-Kuo Lee and Hans A. R. Bluyssen. Editorial: STATs and IRFs in Innate Immunity: From Transcriptional Regulators to Therapeutic Targets. Front. Immunol, 06 August 2019 10:1829 doi: 10.3389/fimmu.2019.01829
4. Ming-Hsun Tsai, Li-Mei Pai and Chien-Kuo Lee Fine-Tuning of Type I Interferon Response by STAT3. Front. Immunol. 2019 10:1448 doi: 10.3389/fimmu.2019.01448 (Review).
5. Ming-Hsun Tsai and Chien-Kuo Lee STAT3 cooperates with phospholipid scramblase 2 to suppress type I interferon response. Front. Immunol. 2018 9:1886 doi:10.3389/fimmu.2018.01886
6. Ting-Ting Chen, Ming-Hsun Tsai, John Kung, Thomas Decker, Kuo-I Lin and Chien-Kuo Lee STAT1 regulates marginal zone B cell differentiation in response to inflammation and infection with blood-borne bacteria. J. Exp. Med. 2016 213(13): 3025-3039.
7. Yi-Ling Chen, Shiun Chang, Ting-Ting Chen and Chien-Kuo Lee Effecient generation of plasmacytoid dendritic cell from common lymphoid progenitors by Flt3 ligand. PLoS One 2015 10(8):e0135217 DOI:10.137/journal.pone.0135217.
8. Yi-Ling Chen, Ting-Ting Chen, Li-Mei Pai, Joanna Wesoly, Hans A. R. Bluyssen and Chien-Kuo Lee A type I IFN/Flt3 ligand axis augments plasmacytoid dendritic cell development from common lymphoid progenitors. J. Exp. Med. 2013 210:2515-2522
9. Wei-Bei Wang, David E. Levy and Chien-Kuo Lee STAT3 negatively regulates type I IFN-mediated antiviral response. J. Immunology 2011 187:2578-2585

Last updated  11/03/2023