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. [Copyright &y& Elsevier]