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Classical Flt3L-dependent dendritic cells control immunity to protein vaccine
Anandasabapathy, Niroshana,Feder, Rachel,Mollah, Shamim,Tse, Sze-Wah,Longhi, Maria Paula,Mehandru, Saurabh,Matos, Ines,Cheong, Cheolho,Ruane, Darren,Brane, Lucas,Teixeira, Angela,Dobrin, Joseph,Mizeni The Rockefeller University Press 2014 The Journal of experimental medicine Vol.211 No.9
<P>DCs are critical for initiating immunity. The current paradigm in vaccine biology is that DCs migrating from peripheral tissue and classical lymphoid-resident DCs (cDCs) cooperate in the draining LNs to initiate priming and proliferation of T cells. Here, we observe subcutaneous immunity is Fms-like tyrosine kinase 3 ligand (Flt3L) dependent. Flt3L is rapidly secreted after immunization; Flt3 deletion reduces T cell responses by 50%. Flt3L enhances global T cell and humoral immunity as well as both the numbers and antigen capture capacity of migratory DCs (migDCs) and LN-resident cDCs. Surprisingly, however, we find immunity is controlled by cDCs and actively tempered in vivo by migDCs. Deletion of Langerin<SUP>+</SUP> DC or blockade of DC migration improves immunity. Consistent with an immune-regulatory role, transcriptomic analyses reveals different skin migDC subsets in both mouse and human cluster together, and share immune-suppressing gene expression and regulatory pathways. These data reveal that protective immunity to protein vaccines is controlled by Flt3L-dependent, LN-resident cDCs.</P>
Flt3 Signaling-Dependent Dendritic Cells Protect against Atherosclerosis
Choi, J.H.,Cheong, C.,Dandamudi, Durga B.,Park, C.,Rodriguez, A.,Mehandru, S.,Velinzon, K.,Jung, I.H.,Yoo, J.Y.,Oh, G.,Steinman, Ralph M. Cell Press 2011 Immunity Vol.35 No.5
Early events in atherosclerosis occur in the aortic intima and involve monocytes that become macrophages. We looked for these cells in the steady state adult mouse aorta, and surprisingly, we found a dominance of dendritic cells (DCs) in the intima. In contrast to aortic adventitial macrophages, CD11c<SUP>+</SUP>MHC II<SUP>hi</SUP> DCs were poorly phagocytic but were immune stimulatory. DCs were of two types primarily: classical Flt3-Flt3L signaling-dependent, CD103<SUP>+</SUP>CD11b<SUP>-</SUP> DCs and macrophage-colony stimulating factor (M-CSF)-dependent, CD14<SUP>+</SUP>CD11b<SUP>+</SUP>DC-SIGN<SUP>+</SUP> monocyte-derived DCs. Both types expanded during atherosclerosis. By crossing Flt3<SUP>-/-</SUP> to Ldlr<SUP>-/-</SUP> atherosclerosis-prone mice, we developed a selective and marked deficiency of classical CD103<SUP>+</SUP> aortic DCs, and they were associated with exacerbated atherosclerosis without alterations in blood lipids. Concomitantly, the Flt3<SUP>-/-</SUP>Ldlr<SUP>-/-</SUP> mice had fewer Foxp3<SUP>+</SUP> Treg cells and increased inflammatory cytokine mRNAs in the aorta. Therefore, functional DCs are dominant in normal aortic intima and, in contrast to macrophages, CD103<SUP>+</SUP> classical DCs are associated with atherosclerosis protection.
Do, Yoonkyung,Koh, Hyein,Park, Chae Gyu,Dudziak, Diana,Seo, Patrick,Mehandru, S.,Choi, Jae-Hoon,Cheong, Cheolho,Park, Steven,Perlin, David S.,Powell, Bradford S.,Steinman, Ralph M. WILEY-VCH Verlag 2010 European journal of immunology Vol.40 No.10
<P>To help design needed new vaccines for pneumonic plague, we targeted the Yersinia pestis LcrV protein directly to CD8α<SUP>+</SUP> DEC-205<SUP>+</SUP> or CD8α<SUP>−</SUP> DCIR2<SUP>+</SUP> DC along with a clinically feasible adjuvant, poly IC. By studying Y. pestis in mice, we could evaluate the capacity of this targeting approach to protect against a human pathogen. The DEC-targeted LcrV induced polarized Th1 immunity, whereas DCIR2-targeted LcrV induced fewer CD4<SUP>+</SUP> T cells secreting IFN-γ, but higher IL-4, IL-5, IL-10, and IL-13 production. DCIR-2 targeting elicited higher anti-LcrV Ab titers than DEC targeting, which were comparable to a protein vaccine given in alhydrogel adjuvant, but the latter did not induce detectable T-cell immunity. When DEC- and DCIR2-targeted and F1-V+ alhydrogel-vaccinated mice were challenged 6 wk after vaccination with the virulent CO92 Y. pestis, the protection level and Ab titers induced by DCIR2 targeting were similar to those induced by F1-V protein with alhydrogel vaccination. Therefore, LcrV targeting to DC elicits combined humoral and cellular immunity, and for the first time with this approach, also induces protection in a mouse model for a human pathogen.</P>
Abernathy, C.R.,Gila, B.P.,Onstine, A.H.,Pearton, S.J.,Kim, Ji-Hyun,Luo, B.,Mehandru, R.,Ren, F.,Gillespie, J.K.,Fitch, R.C.,Seweel, J.,Dettmer, R.,Via, G.D.,Crespo, A.,Jenkins, T.J.,Irokawa, Y. The Institute of Electronics and Information Engin 2003 Journal of semiconductor technology and science Vol.3 No.1
Both MgO and $Sc_2O_3$ are shown to provide low interface state densities (in the $10^{11}{\;}eV^{-1}{\;}cm{\;}^{-2}$ range)on n-and p-GaN, making them useful for gate dielectrics for metal-oxide semiconductor(MOS) devices and also as surface passivation layers to mitigate current collapse in GaN/AlGaN high electron mobility transistors(HEMTs).Clear evidence of inversion has been demonstrated in gate-controlled MOS p-GaN diodes using both types of oxide. Charge pumping measurements on diodes undergoing a high temperature implant activation anneal show a total surface state density of $~3{\;}{\times}{\;}10^{12}{\;}cm^{-2}$. On HEMT structures, both oxides provide effective passivation of surface states and these devices show improved output power. The MgO/GaN structures are also found to be quite radiation-resistant, making them attractive for satellite and terrestrial communication systems requiring a high tolerance to high energy(40MeV) protons.