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Lung dendritic cells induce migration of protective T cells to the gastrointestinal tract
Ruane, Darren,Brane, Lucas,Reis, Bernardo Sgarbi,Cheong, Cheolho,Poles, Jordan,Do, Yoonkyung,Zhu, Hongfa,Velinzon, Klara,Choi, Jae-Hoon,Studt, Natalie,Mayer, Lloyd,Lavelle, Ed C.,Steinman, Ralph M.,Mu The Rockefeller University Press 2013 The Journal of experimental medicine Vol.210 No.9
<P>Developing efficacious vaccines against enteric diseases is a global challenge that requires a better understanding of cellular recruitment dynamics at the mucosal surfaces. The current paradigm of T cell homing to the gastrointestinal (GI) tract involves the induction of α4β7 and CCR9 by Peyer’s patch and mesenteric lymph node (MLN) dendritic cells (DCs) in a retinoic acid–dependent manner. This paradigm, however, cannot be reconciled with reports of GI T cell responses after intranasal (i.n.) delivery of antigens that do not directly target the GI lymphoid tissue. To explore alternative pathways of cellular migration, we have investigated the ability of DCs from mucosal and nonmucosal tissues to recruit lymphocytes to the GI tract. Unexpectedly, we found that lung DCs, like CD103<SUP>+</SUP> MLN DCs, up-regulate the gut-homing integrin α4β7 in vitro and in vivo, and induce T cell migration to the GI tract in vivo. Consistent with a role for this pathway in generating mucosal immune responses, lung DC targeting by i.n. immunization induced protective immunity against enteric challenge with a highly pathogenic strain of <I>Salmonella</I>. The present report demonstrates novel functional evidence of mucosal cross talk mediated by DCs, which has the potential to inform the design of novel vaccines against mucosal pathogens.</P>
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>