Abstract
Migration of leukocytes from the skin to lymph nodes (LNs) via afferent lymphatic vessels (LVs) is pivotal for adaptive immune responses1,2. Circadian rhythms have emerged as important regulators of leukocyte trafficking to LNs via the blood3,4. Here, we demonstrate that dendritic cells (DCs) have a circadian migration pattern into LVs, which peaks during the rest phase in mice. This migration pattern is determined by rhythmic gradients in the expression of the chemokine CCL21 and of adhesion molecules in both mice and humans. Chronopharmacological targeting of the involved factors abrogates circadian migration of DCs. We identify cell-intrinsic circadian oscillations in skin lymphatic endothelial cells (LECs) and DCs that cogovern these rhythms, as their genetic disruption in either cell type ablates circadian trafficking. These observations indicate that circadian clocks control the infiltration of DCs into skin lymphatics, a process that is essential for many adaptive immune responses and relevant for vaccination and immunotherapies.
Highlights
Steady-state migration of dermal dendritic cells (DCs) into afferent lymphatic vessels (LVs) is tightly regulated by a variety of promigratory factors, including the CCL21–chemokine receptor 7 (CCR7) chemokine axis and the adhesion molecules LYVE1, CD99 and JAM-A1,2,5–12
The diurnal migration of CD11c+ DCs into LVs was detected after the topical application of fluorescein isothiocyanate (FITC), an inflammatory stimulus (Fig. 1c), indicating that the migration differences were maintained during inflammation
In situ whole-mount staining of ears identified that CD11c+langerin– CD103– dermal conventional DCs and CD11c+langerin+ Langerhans cells (LCs) preferentially migrated into LVs at ZT7 compared to at ZT19, while very few CD11c+langerin–CD103+
Summary
We present here evidence that the migration of DCs into skin lymphatics is a rhythmic process. We found that CCL21, CCR7 and LYVE-1 are under the direct control of the circadian clock gene BMAL1, implicating the clock as an essential and broad regulator of DC migration. As this process is fundamental for the generation of adaptive immunity, it should prove useful to exploit in vaccination and immunotherapeutic regimens, considering that rhythmicity in innate and adaptive immune responses is maintained in inflammatory reactions[13,14,21,25,26,27]. Received: 11 May 2021; Accepted: 31 August 2021; Published online: 18 October 2021
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