The development of distinct dendritic cell(DC)subsets,namely,plasmacytoid DCs(pDCs)and conventional DC subsets(cDC1s and cDC2s),is controlled by specific transcription factors.IRF8 is essential for the fate specificat...The development of distinct dendritic cell(DC)subsets,namely,plasmacytoid DCs(pDCs)and conventional DC subsets(cDC1s and cDC2s),is controlled by specific transcription factors.IRF8 is essential for the fate specification of cDC1s.However,how the expression of Irf8 is regulated is not fully understood.In this study,we identified TRIM33 as a critical regulator of DC differentiation and maintenance.TRIM33 deletion in Trim33fl/fl Cre-ERT2 mice significantly impaired DC differentiation from hematopoietic progenitors at different developmental stages.TRIM33 deficiency downregulated the expression of multiple genes associated with DC differentiation in these progenitors.TRIM33 promoted the transcription of Irf8 to facilitate the differentiation of cDC1s by maintaining adequate CDK9 and Ser2 phosphorylated RNA polymerase II(S2 Pol II)levels at Irf8 gene sites.Moreover,TRIM33 prevented the apoptosis of DCs and progenitors by directly suppressing the PU.1-mediated transcription of Bcl2l11,thereby maintaining DC homeostasis.Taken together,our findings identified TRIM33 as a novel and crucial regulator of DC differentiation and maintenance through the modulation of Irf8 and Bcl2l11 expression.The finding that TRIM33 functions as a critical regulator of both DC differentiation and survival provides potential benefits for devising DC-based immune interventions and therapies.展开更多
基金The Ministry of Science and Technology of China National Key Research Projects provided grants 2019YFA0508502 and 2022YFC2505001 to LWThe National Natural Science Foundation of China funded grant 31991174 to LW+4 种基金The National Natural Science Foundation of China provided Basic Research Center grant 82388101 to LWThe National Natural Science Foundation of China provided grant 81801641 to JLThe National Natural Science Foundation of China provided grant 31800769 to ZHThe Ministry of Science and Technology of China National Key Research Projects provided grants 2022YFC2505002 to TWFunding from the Tsinghua-Peking Center for Life Sciences to LW is acknowledged.
文摘The development of distinct dendritic cell(DC)subsets,namely,plasmacytoid DCs(pDCs)and conventional DC subsets(cDC1s and cDC2s),is controlled by specific transcription factors.IRF8 is essential for the fate specification of cDC1s.However,how the expression of Irf8 is regulated is not fully understood.In this study,we identified TRIM33 as a critical regulator of DC differentiation and maintenance.TRIM33 deletion in Trim33fl/fl Cre-ERT2 mice significantly impaired DC differentiation from hematopoietic progenitors at different developmental stages.TRIM33 deficiency downregulated the expression of multiple genes associated with DC differentiation in these progenitors.TRIM33 promoted the transcription of Irf8 to facilitate the differentiation of cDC1s by maintaining adequate CDK9 and Ser2 phosphorylated RNA polymerase II(S2 Pol II)levels at Irf8 gene sites.Moreover,TRIM33 prevented the apoptosis of DCs and progenitors by directly suppressing the PU.1-mediated transcription of Bcl2l11,thereby maintaining DC homeostasis.Taken together,our findings identified TRIM33 as a novel and crucial regulator of DC differentiation and maintenance through the modulation of Irf8 and Bcl2l11 expression.The finding that TRIM33 functions as a critical regulator of both DC differentiation and survival provides potential benefits for devising DC-based immune interventions and therapies.
