Anandasabapathy, NiroshanaFeder, RachelMollah, ShamimTse, Sze-WahLonghi, Maria PaulaMehandru, SaurabhMatos, InesCheong, CheolhoRuane, DarrenBrane, LucasTeixeira, AngelaDobrin, JosephMizenina, OlgaPark, Chae GyuMeredith, MatthewClausen, Björn E.Nussenzweig, Michel C.Steinman, Ralph M.2015-03-022014Anandasabapathy, N., R. Feder, S. Mollah, S. Tse, M. P. Longhi, S. Mehandru, I. Matos, et al. 2014. “Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.” The Journal of Experimental Medicine 211 (9): 1875-1891. doi:10.1084/jem.20131397. http://dx.doi.org/10.1084/jem.20131397.0022-1007http://nrs.harvard.edu/urn-3:HUL.InstRepos:14065460DCs 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+ 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.en-USJournal Article2015-03-0210.1084/jem.20131397