The Regulatory Effects Of Foxpl On The Differentiation And Function Of Dendritic Cells And Its Underlying Mechanisms

Dendritic cells (DCs) are the most effective antigen presenting cells of themammalian immune system. As DCs’ functions are strongly associated with their state ofdifferentiation and development, investigation of key transcription factor during theirdifferentiation and development becomes the hot issue in immunology. It is widelyaccepted that Foxp3, a member of Forkhead box (Fox) superfamily, is the most importanttranscription factor in Treg’s differentiation and development. Autoimmune diseases canbe induced after the gene mutation of Foxp3. Previously, Sequencing Analysis has beenperformed to identify the various transcription factors of DCs in our lab. We wereintrigued by one of the Forkhead box superfamily members, Foxp1. Foxp1has beenproveded that could take part in B cells’ and monocytic differentiation and regulatemacrophages’ functions. It has been reported that during the differentiation of peripheralblood monocytes to tissue macrophages the expression of Foxp1is downregulated. WhileDCs and macrophages have the common precursor, so we detected the expression ofFoxp1during DCs’ maturation process. Our results showed that Foxp1is upregulated.Herein, we suppose that Foxp1might be associated with DCs’ deferentiation anddevelopment.In present study, we first observed that the expression of Foxp1protein wasupregulated during the maturation of bone marrow derived DCs. Three pairs of Foxp1siRNA had been designed to examine which one could most effectively interfere theexpression of Foxp1protein. We also constructed recombinant adenovirus (Ad-simFoxp1)carrying specific interfering RNA (siRNA) to examine the functions of DCs afterinterfering the expression of Foxp1. The results showed that less expression of CD80andCD86was downregulated in Ad-simFoxp1modified DCs. Compared with the controlgroup, the Ad-simFoxp1modified DCs showd stronger phagocytic ability but producedmuch less cytokines. These DCs had limited ability to induce T cells proliferation in theMLR system and peptide-specific CD4+T cells proliferation. These results indicated thatFoxp1can regulate the functions of DCs.By using the EAE model, we then examined the effects of Ad-simFoxp1modifiedDCs in induction of this kind of autoimmune disease. The results showed that after injection of those pretreated DCs into normal C57BL/6mice intraperitoneally, the onsetof disease was markedly delayed in Ad-simFoxp1modified DCs pretreated groupcompared with the control group, and the clinical nervous system function was alsogreatly improved with lower clinical score. Our results demonstrated that Ad-simFoxp1modified DCs probably play a role in protecting C57BL/6mice from the inducrion ofEAE in vivo.In summary, our study showed that Foxp1might be a novel transcription factor thatcould induce DCs’ differentiation and development of DCs. It could regulate DCs’functions by downregulation of CD80and CD86, and cytokines. Antigen-specificimmune tolerance could be induced by Ad-simFoxp1modified DCs in vivo. It showedclinical potential in treatment of some immune related diseases.