title: Francisella tularensis LVS-induced Interleukin-12 p40 cytokine production mediates dendritic cell migration through IL-12 Receptor β1.
abstract: Three cytokines use the IL-12p40 cytokine subunit namely: IL-12p70 (IL-12-comprised of IL-12p40 and IL-12p35), IL-23 (comprised of the IL-12p40 and IL-23p19 subunits) and homodimeric IL-12p40 (IL-12(p40)(2)). Following activation, immature dendritic cells (DCs) upregulate the chemokine receptor Chemokine-C-Receptor 7 (CCR7), and migrate in response to homeostatic chemokines such as chemokine (C-C motif) ligand 19 (CCL19). Induction of the cytokine IL-12p40 in response to pathogen-exposure, likely in its homodimeric form, is one of the primary events that mediates migration of DCs in response to CCL19. Here we show that following exposure to Francisella tularensis Live Vaccine Strain (LVS), DCs produce IL-12p40 and promote the migration of DCs to the chemokine CCL19 in an IL-12Rβ1- and IL-12p(40)(2)-dependent manner. Induction of IL-12p40 and resulting chemokine responsiveness in DCs is TLR2-dependent and coincides with the uptake of F. tularensis LVS and activation of DCs. Importantly, we show that IL-12Rβ1 signaling is required for DC migration from the lung to the draining lymph node following F. tularensis LVS exposure and coincides with accumulation of IL-12p40 expressing DCs in the draining lymph nodes. Together, these findings illustrate that IL-12p40 is induced rapidly in response to F. tularensis LVS and is required for DC migration through an IL-12Rβ1-IL-12(p40)(2) dependent mechanism.
authors.affiliation: Division of Infectious Diseases, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA.
authors.forename: Samantha R
authors.initials: SR
authors.lastname: Slight
authors.forename: Yinyao
authors.initials: Y
authors.lastname: Lin
authors.forename: Michelle
authors.initials: M
authors.lastname: Messmer
authors.forename: Shabaana A
authors.initials: SA
authors.lastname: Khader
mesh_terms: D000818:Animals; D002465:Cell Movement; D054415:Chemokine CCL19 / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000166:cytology / Q000276:immunology*; D005604:Francisella tularensis / Q000276:immunology*; D053711:Interleukin-12 Receptor beta 1 Subunit / Q000276:immunology*; D053762:Interleukin-12 Subunit p40 / Q000096:biosynthesis* / Q000276:immunology*; D008168:Lung / Q000276:immunology; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D054400:Receptors, CCR7 / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000276:immunology
chemical_list: C515461:Ccl19 protein, mouse; C515371:Ccr7 protein, mouse; D054415:Chemokine CCL19; D053711:Interleukin-12 Receptor beta 1 Subunit; D053762:Interleukin-12 Subunit p40; D054400:Receptors, CCR7; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2