SMAD3 Determines Conventional versus Plasmacytoid Dendritic Cell Fates

Yoon, J.-H.; Bae, E.; Sudo, K.; Han, J. S.; Park, S. H.; Nakae, S.; Yamashita, T.; Lee, I.-K.; Ju, J. H.; Matsumoto, I.; Sumida, T.; Kuroda, M.; Miyazawa, K.; Kato, M.; Mamura, M.

doi:10.1101/715060

bioRxiv · 10.1101/715060

SMAD3 Determines Conventional versus Plasmacytoid Dendritic Cell Fates

Yoon, J.-H.·Bae, E.·Sudo, K.·Han, J. S.·Park, S. H.·Nakae, S.·Yamashita, T.·Lee, I.-K.·Ju, J. H.·Matsumoto, I.·Sumida, T.·Kuroda, M.·Miyazawa, K.·Kato, M.·Mamura, M.

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Abstract

Transforming growth factor (TGF)-{beta} plays crucial roles in differentiation of dendritic cells (DC). However, molecular mechanisms how TGF-{beta} regulates DC differentiation remain largely unknown. Here, we show that selective repression of one of the TGF-{beta} receptor-regulated SMADs (R-SMADs), SMAD3 directs conventional DC (cDC) differentiation, whereas maintenance of SMAD3 is indispensable for plasmacytoid DC (pDC) differentiation. Expression of SMAD3 was specifically downregulated in CD115+ common DC progenitor (CDP), pre-cDCs and cDCs. SMAD3 deficient mice showed a significant reduction in pre-pDCs and pDCs with increased CDP, pre-cDCs and cDCs. SMAD3 upregulated the pDC-related genes: SPI-B, E2-2 and IKAROS, while it repressed FLT3 and the cDC-related genes: IRF4 and ID2. STAT3 and a SMAD transcriptional co-repressor, c-SKI repressed SMAD3 for cDC differentiation, whereas canonical SMAD-mediated TGF-{beta} signalling maintained SMAD3 for pDC differentiation. Thus, SMAD3 is the pivotal determinant to bifurcate cDC and pDC differentiation in the steady-state condition.

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Yoon, J.-H., Bae, E., Sudo, K., Han, J. S., Park, S. H., Nakae, S., Yamashita, T., Lee, I.-K., Ju, J. H., Matsumoto, I., Sumida, T., Kuroda, M., Miyazawa, K., Kato, M., Mamura, M.. 2019-07-25. SMAD3 Determines Conventional versus Plasmacytoid Dendritic Cell Fates. https://doi.org/10.1101/715060

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