The mechanisms how Smad-mediated transforming growth factor-β (TGF-β) signalling regulates dendritic cells (DCs) remain largely unknown, despite its crucial regulatory roles in the differentiation and activation of DCs. Here, we show that STAT3/c-Ski-induced downregulation of Smad3 during differentiation selects Smad2 as the specific TGF-β receptor-regulated Smad (R-Smad) to suppress the immunogenicity of DCs. Smad3 transcribed by unphosphorylated Smad2/3 prevented the progenitor cells from DC differentiation with repression of Flt3, IRF4 and STAT3. Repression of Smad3 by synergy of phosphorylated STAT3 and c-Ski was essential for DC differentiation. TGF-β suppressed DC activation via Smad2, hence DC-specific Smad2 deletion enhanced anti-lymphoma effector functions of cytotoxic T lymphocytes (CTLs) and type 1 helper T (Th1) cells in a mouse EL4 lymphoma model. Our findings reveal stepwise regulatory roles of R-Smads in DC regulation: Smad3 inhibits differentiation and Smad2 suppresses immunogenicity.

Citation Format: Jeong-Hwan Yoon, Eunjin Bae, Katsuko Sudo, Masakatsu Takanashi, Jin Soo Han, Seok Hee Park, Michael Weinstein, Susumu Nakae, Tadashi Yamashita, In-Kyu Lee, Ji Hyeon Ju, Takayuki Sumida, Masahiko Kuroda, Keiji Miyazawa, Mitsuyasu Kato, Mizuko Mamura. Selection of Smad2 for TGF-β to suppress dendritic cells by STAT3/c-Ski-induced repression of Smad3 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4628. doi:10.1158/1538-7445.AM2017-4628