Classical Flt3L-dependent dendritic cells control immunity to protein vaccine.

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(+) 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.

Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells.

Skin-derived dendritic cells (DCs) are potent antigen-presenting cells with critical roles in both adaptive immunity and tolerance to self. Skin DCs carry antigens and constitutively migrate to the skin-draining lymph nodes (LNs). In mice, Langerin-CD11b- dermal DCs are a low-frequency, heterogeneous, migratory DC subset that traffics to LNs (Langerin-CD11b- migDCs). Here, we build on the observation that Langerin-CD11b- migDCs are Fms-like tyrosine kinase 3 ligand (Flt3L) dependent and strongly Flt3L responsive, which may relate them to classical DCs. Examination of DC capture of FITC from painted skin, DC isolation from skin explant culture, and from the skin of CCR7 knockout mice, which accumulate migDCs, demonstrate these cells are cutaneous residents. Langerin-CD11b- Flt3L-responsive DCs are largely CD24(+) and CX3CR1(low) and can be depleted from Zbtb46-DTR mice, suggesting classical DC lineage. Langerin-CD11b- migDCs present antigen with equal efficiency to other DC subsets ex vivo, including classical CD8α cDCs and Langerin+CD103+ dermal DCs. Finally, transcriptome analysis suggests a close relationship with other skin DCs, and a lineage relationship with other classical DCs. This work demonstrates that Langerin- CD11b- dermal DCs, a previously overlooked cell subset, may be an important contributor to the cutaneous immune environment.

Diabetic cardiomyopathy: signaling defects and therapeutic approaches.

Diabetes mellitus is the world's fastest growing disease with high morbidity and mortality rates, predominantly as a result of heart failure. A significant number of diabetic patients exhibit diabetic cardiomyopathy; that is, left ventricular dysfunction independent of coronary artery disease or hypertension. The pathogenesis of diabetic cardiomyopathy is complex, and is characterized by dysregulated lipid metabolism, insulin resistance, mitochondrial dysfunction and disturbances in adipokine secretion and signaling. These abnormalities lead to impaired calcium homeostasis, ultimately resulting in lusitropic and inotropic defects. This article discusses the impact of these hallmark factors in diabetic cardiomyopathy, and concludes with a survey of available and emerging therapeutic modalities.

Disregulated RhoGTPases and actin cytoskeleton contribute to the migration defect in Lis1-deficient neurons.

Lissencephaly is a severe brain malformation caused by impaired neuronal migration. Lis1, a causative gene, functions in an evolutionarily conserved nuclear translocation pathway regulating dynein motor and microtubule dynamics. Whereas microtubule contributions to neuronal motility are incompletely understood, the actin cytoskeleton is essential for crawling cell movement of all cell types investigated. Lis1 haploinsufficiency is shown here to also result in reduced filamentous actin at the leading edge of migrating neurons, associated with upregulation of RhoA and downregulation of Rac1 and Cdc42 activity. Disruption of RhoA function through pharmacological inhibition of its effector kinase, p160ROCK, restores normal Rac1 and Cdc42 activity and rescues the motility defect in Lis1+/- neurons. These data indicate a previously unrecognized role for Lis1 protein in neuronal motility by promoting actin polymerization through the regulation of Rho GTPase activity. This effect of Lis1 on GTPases does not appear to occur through direct Lis1 binding of Rho, but could involve Lis1 effects on Rho modulatory proteins or on microtubule dynamics.